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CHAPTER ONEIntroductionLearning Objectives•Be able to conceptualize the “information explosion” and how it relates to the brain sciences.•Be able to describe pharmacodynamics and pharmacokinetics.•Be able to articulate the benefits of an integrative approach to psychopharmacology.ENCOURAGEMENT TO THE READERSome of you may begin this book with some anxiety because this is a new area for you. You may imagine that psychopharmacology is exclusively a “hard science,” and perhaps you don’t think of yourself as a “hard science” kind of person. You may even feel uncertain about your ability to master basic psychopharmacological concepts. First, let us assure you one more time that our goal is to make this topic accessible to readers who are practicing as or studying to be mental health professionals, many of whom may not have a background in the physical or organic sciences. Second, we recommend to those teaching a course in psychopharmacology that, because of the rapid nature of change in the field, teaching styles that rely on memorization are of limited use in this area. We recommend helping students master basic concepts and then applying these concepts to cases. To facilitate that process, we supply cases and objectives/review questions for main sections of the book. Finally, we invite you students to join us in an incredible journey centering on the most complex organ known to humanity—the human mind and brain. We hope you can revel in the complexity of the brain and the sheer magnitude of its power. We hope you can resist the temptation to want simple and concrete answers to many of the questions this journey will raise. We also hope you learn to appreciate the ambiguous nature of “mind” and its relationship to the brain. As authors and researchers who have traveled this path before us will attest, there are no simple or even known answers to many of the questions that arise (Grilly & Salmone, 2011; Schatzberg & Nemeroff, 1998). We encourage a mixture of trying to comprehend the information while dwelling in the mystery that is the context for the information. Before moving on, we offer a mantra to help you implement this recommendation.A MANTRAEven though psychopharmacology is in its embryonic stage, it is a vast and complex topic. Several years ago I (Ingersoll) engaged in some multicultural counseling training with Paul Pederson. In that training, Dr. Pederson commented, “Culture is complex, and complexity is our friend.” We offer a paraphrase as a mantra for psychopharmacology students: “Reality is complex, and complexity is our friend.” We remind the reader of this mantra throughout the book. You might try saying it aloud right now: “Reality is complex, and complexity is our friend.” If you reach a passage in this book that is challenging for you or that arouses anxiety, stop, take a deep breath, and practice the mantra.The primary audience for this book is mental health clinicians who may not have had much training in biology, neurology, and psychopharmacology. This includes counselors, psychologists, clinical social workers, marriage and family therapists, and substance abuse counselors. We will refer specifically to these different mental health professionals throughout the book as well as including all of them in the phrase “mental health professionals.” Although there are significant differences in the training models of these different professionals, they all draw on the same knowledge base when treating clients in school or clinical settings. We also want to add that there are several labels used to describe the therapeutic relationships clients have with mental health professionals. These labels include “counseling,” “therapy,” “talk therapy,” “psychosocial interventions,” and “psychotherapy.” There is great debate across the mental health professions about whether and how these labels differ, but in this book we use them synonymously for the sake of simplicity. While reading this book, you will notice technical terms highlighted with bold print the first time they appear. These terms are defined in the Glossary at the end of the book. Although not all key terms are highlighted, those that nonmedical mental health professionals are less likely to have been exposed to are defined in the Glossary. We encourage you to keep a dictionary handy for other terms that may be new to you. If you come across a word you do not understand, stop reading and check the definition in the glossary or a dictionary. Many readers skip over unfamiliar words assuming the meaning will become clear in a later sentence. Clarifying unfamiliar words when they occur adds to the enjoyment of reading the book and facilitates a better understanding of the topic.SCIENTIFIC TRUTH AND THE ACCELERATION OF KNOWLEDGEIt is no secret that knowledge accumulation is accelerating. We are familiar with the label “information explosion” to describe this phenomenon. In the early 1970s, the French economist Georges Anderla (1973, 1974) prepared a statistical estimate of how quickly knowledge has been growing, based on a variety of indicators. According to Anderla, if you begin in the year 1 C.E. (which stands for Current or Common, Era) it took 1500 years for knowledge to double. The second doubling took only 250 years (1750). The third doubling took only 150 years (1900), the fourth 50 years (1950), and the fifth doubling only 10 years (1960). If there is any accuracy in Anderla’s model, knowledge began doubling almost monthly in the late 20th century (Wilson, 1992). Increase in knowledge about the human brain is particularly pronounced.The final decades of the 20th century unearthed more knowledge about the human brain than all prior centuries combined. One of the most exciting fields benefiting from these developments is psychopharmacology.Pharmacologyis the science of the preparation, uses, and effects of drugs.Psychopharmacologyis the branch of pharmacology related to the psychological effects of drugs and the use of drugs to treat symptoms of mental and emotional disorders. These drugs are calledpsychotropic medications. “Psyche” colloquially refers to “mind,” and “tropic” means “acting on” or “moving toward” but many in the field would say these medications act on the brain and this affects the mind.Developing neuroscience technologies have helped accelerate brain research and change in the field of psychopharmacology by letting scientists peer more deeply into the brain and nervous system. The latest technological advances include positron emission tomography (PET) scans, magnetic resonance imaging (MRI), Diffusion Tensor Imaging (DTI), Voxel-Based Morphometry, and magneto-encephalography. PET scans for brain functions work thus: The technician injects a radioactive form of oxygen into a person and then asks the person to perform a particular task under a PET scanner. Because the brain area most active during the task requires more oxygen, the PET scanner can trace the radioactive oxygen to those sites in the brain used in the task. The computer scanner then generates a picture that maps the brain activity. MRI scans generate images by magnetizing hemoglobin (the iron-containing coloredmatter in red blood corpuscles that carry oxygen to tissues) and by tracing changes in blood oxygen levels in the brain. Like the PET scan, MRI images of the brain can be used for diagnostic or research purposes. DTI is a type of MRI that can highlight microstructural changes in the white matter of the brain or glial cells (Emsell & McDonald, 2009). This is becoming more important because we discovered that, far from being only glue or insulation for neuronal axons (gliacomes from the Greek word forglue), glial cells actually send neurotransmission and communicate with other cells (Fields, 2009, 2010; Sasaki, Matuski, & Ikegaya, 2011).Magnetoencephalography measures the magnetic field associated with electrical currents in the brain to trace activity levels across brain structures when subjects are engaged in a particular task (Bloom, Nelson, & Lazerson, 2001).There are also multiple techniques for extracting information from MRI scans. The most common quantitative techniques are “region of interest” (ROI) and computational morphometry studies. In ROI analysis, a trained rater manually traces a brain region of interest using “boundary rules” to compare sizes between different brains scanned.Computational morphometryis an automated method of comparing brain structures between different populations in a study. The most common variation is called voxel-based morphometry (VBM), which allows viewing of gray matter, white matter, and cerebrospinal fluid (Emsell & McDonald, 2009).1Voxel-based morphometry is neuroimaging analysis technique that uses a type of mapping (statistical parametric mapping) to identify regions of interest in the brain and calculate their volume. Finally, there are also deformation-based morphometry (DBM) and tensor-based morphometry (TBM). Both techniques are used to compare brain structures, but they rest upon different theoretical assumptions.Computer technology has also enabled pharmaceutical researchers to generate three-dimensional models of brain cell receptors and the drug molecules that bind to them. Brain-scanning technologies have allowed us to see how the drugs act on the nervous system (pharmacodynamicscovered inChapter Two) and how the body metabolizes and eliminates drugs (pharmacokineticscovered more extensively inChapter Three). These are only some of the advances that have contributed to the exponential increase in the number of drugs developed annually.Despite the explosion of advances in psychopharmacology in the last 30 years, the field can still be thought of as in an embryonic stage (Advokat, Comaty, & Julien, 2014). Although scientists know a lot about the physiological mechanisms of many psychotropic medications, we know little about how they actually change mood. Researchers are just now beginning to explore how the effects of psychotropic medication differ depending on the age, sex, and race of the person taking them (Heinrich & Gibbons, 2001). Although Western society is emerging from a postmodern era where multiculturalism was heavily emphasized, little research has been done on differing cultural worldviews regarding psychotropic agents, let alone how such agents differentially affect people of various racial and ethnic backgrounds. In addition, people are now rethinking whether current diagnostic categories for mental and emotional disorders apply to younger children (Ingersoll & Marquis, 2014; McClure, Kubiszyn, & Kaslow, 2002a) and how medications affect the dozens of developmental variables in this age group. Although the Human Genome Project has initiated efforts to understand human DNA, in the late 20th century scientists were still unclear about the role of over 90% of human DNA (Suurkula, 1996). In 2012, teams of scientists agreed that much of the DNA previously thought to be “junk” are actually “switches” that regulate how genes work or turn “off” and “on” (Doolittle, 2013). Efforts to describe the human genetic code and mechanisms of gene expression hold great promise for drug development, but there is still a great deal to be learned.As recently as 30 years ago, psychopharmacology was a medical subspecialty for psychiatrists in particular. At that time, nonmedical mental health providers could ethically practice with little knowledge of psychotropic medications. As long as they had a medical professional to whom they could refer clients, their knowledge of psychotropic medications could be minimal. This is no longer the case. Most (if not all) mental health professionals work with clients taking psychotropic medications and need to be knowledgeable about the drugs their clients are taking. The integrative perspective we emphasize in this book provides a template that, when applied properly, suggests that understanding the physiological properties of psychotropic medications is merely the beginning of the journey. We use the integrative Model to address many pressing issues rarely discussed in books on psychopharmacology. For example, most psychopharmacology books simply discuss what medications are used for particular symptoms but do not address how to deal with cultural issues that may influence a client’s resistance to taking a prescribed medication. Another example is the place ofdirect-to-consumer advertising. Although mental health professionals may know that changes in federal law in the 1980s allowed pharmaceutical companies to advertise directly to consumers via television ads and other media, they may not know that there is a fierce debate over whether such advertising for psychotropic medications is ethical.Pharmacologists working in controlled conditions in laboratories may have the luxury of limiting their focus to interactions between drug molecules and neurotransmitters. But mental health professionals in the field must understand clients’ perceptions and subjective experiences of taking medications, cultural views of psychotropic medications, group differences in response to the medications (according to sex, age, race, etc.), developmental considerations, socioeconomic institutions that mediate access to medications, and competing worldviews and theories on what causes mental health symptoms. The four perspectives of our integrative framework requires consideration of these topics and sets this book apart from other books on psychopharmacology. Although this consideration requires more effort, it contributes to a well-rounded knowledge of psychopharmacology that translates into better clinical practice.Review Questions•What is meant by “information explosion” and how is it reflected in psychopharmacology?•Describe pharmacodynamics and pharmacokinetics.•What are the benefits of an integrative approach to psychopharmacology?CHAPTER ONE: SECTION TWOLearning Objectives•Be able to describe why therapists need more than just a physiological or medical understanding of psychotropic medications.•Discuss the differences between what is commonly thought of as “mind” and what is thought of as “brain.”Everybody Is Right (About Something): The Many Faces of TruthHistory shows that extremists, despite the strength of their convictions, are rarely correct (Radin, 1997, p. 205).In this book, we consider multiple dimensions of and perspectives on psychopharmacology. Although it would be convenient to state that all mental and emotional symptoms derive from some malfunction of brain chemistry, there is no evidence to support this statement. Many people are surprised to hear this, so it is important to restate: There is no evidence that all mental and emotional symptoms derive from somemalfunction or imbalanceof brain chemistry. Today pharmaceutical companies advertise directly to consumers and often give the impression thatpsychological disorders are really “medical disorders” that can be alleviated with a particular medication, much as antibiotics can alleviate a bacterial infection. If psychological disorders were like medical disorders, then studying the brain, brain chemistry, and scientific method would suffice. Even theInternational Classification of Diseases, tenth edition(ICD-10) has a separate volume for mental and behavioral disorders (WHO, 1992). So although the medical model provides an important perspective, we also need to study the mind, the sociocultural contexts in which mind and brain function, and the consciousness underlying mind and brain.The entire truth of psychopharmacology cannot be explored solely through scientific method. Like a diamond, truth has many facets, which are complementary (but not necessarily competing). As philosopher Ken Wilber (2003) notes, no mind is capable of 100% error, so everyone is right about something but not everyone is equally right about everything. Given that insight, exploring the different perspectives of psychopharmacology need not produce warring factions championing mutually exclusive theories ofetiologyand treatment. Taking different perspectives in exploring psychopharmacology reveals different truths about it.Lest you think we are lapsing into some type ofradical constructivismorrelativism(we are not), consider these questions: What sort of blood test would you use to determine your political philosophy? How might exploring your feelings about your mother help diagnose a streptococcus infection? How can a firsthand understanding of a person’s religion be used to tell you how much money he or she earns? How could data about your yearly income be used as an indicator of your sexual orientation? These questions are meaningless, because each proposes an incorrect tool for finding the answer. Because different perspectives reveal different faces of truth, they require tools matched to the task. There are different forms of truth and knowledge and different tools are employed in exploring them. We emphasize this point because many people believe that medical science (or science in general) is the only tool and that it can solve any problem.The Medical Model PerspectiveThe perspective of medical science (and science in general) clearly reflects one type of truth, and we draw amply from it in this book. Whereas a relativist would say that one perspective or type of truth is just as good as another for any job, we maintain that some perspectives and tools are better than others for particular tasks. Everyone knows that no blood test can determine a person’s political philosophy. Does this mean one’s preference for a political philosophy does not exist? No. It simply means a blood test is not a good tool to use to explore the issue. In this case, dialogue is far better than a blood test. To find out a person’s political philosophy, you talk with the person to learn what his or her political philosophy is. Regarding the diagnosis of streptococcus infection, a throat culture is a far better test than discussing feelings about one’s mother.Scientific truth is objective truth that can be verified by some observable measurement. This is the type of truth emphasized by the tools of scientific method, the medical model, and most psychopharmacology books. The perspective of scientific truth is an important cornerstone of psychopharmacology. This is what we are referring to as themedical model perspective. It is characterized by its focus on objective, measurable data related to individuals. Although labeled “medical model” for the purposes of this book, this perspective also includes schools of psychology that rely heavily on objective measurement (such as behaviorism). In psychopharmacology, the medical model perspective helps us understand parts of the brain that seem correlated with symptoms of mental or emotional disorders and things such as the molecular structure of drugs. But mental health professionals are concerned with more than the correlations of symptoms with brain functions or the molecular structures of drugs. As professionals, we are also concerned withhow clients feelabout taking medications, how and whether psychotropic medications alter their consciousness, relevant cultural issues that may affect their attitudes or increase their preference for alternatives to psychotropic medications, aspects of group membership (race, sex) that may predict differential responses to psychotropicmedications, as well as how our clients’ place in society affects their ability to get the drugs they may need.The Psychological PerspectiveOther perspectives complement the medical model and help mental health professionals build a well-rounded understanding of psychopharmacology. These other perspectives reveal other faces of truth that the medical model is not equipped to explore but that are equally important for mental health professionals. As Wilber (1997) noted, the techniques of the medical model perspective can trace the electrical currents in a subject’s brain but can only give scientific verification about the electrical activity in that brain—they cannot tell whether the person is thinking about opening a homeless shelter or robbing a liquor store. Further, there is no evidence that the experience of consciousness is caused solely by electrical activity in our brains (Chalmers, 1995).Information about what other people (including our clients) are thinking can only be obtained through truthful dialogue with them. This introduces the second perspective we use in this book, thepsychological perspective. Psychology’s name is derived from the goal of studying the mind or soul. Despite that origin, it has evolved into the scientific study of mind and behavior and has come to greatly resemble the medical model. Schwartz and Begley (2002) assert that psychologists have become overly attached to a version of the medical model that dismisses conscious experience and focuses only on what is observable or measurable. They conclude, “Surely there is something deeply wrong, both morally and scientifically, with a school of psychology whose central tenet is that people’s conscious life experience … is irrelevant” (p. 6). It is that conscious experience that we are referring to when we use the phrase “psychological perspective” or what consciousness feels like from the inside. We include the psychological perspective because clients’phenomenologicalexperiences of the world cannot be dismissed as irrelevant and are often a key ingredient in their growth.Our psychological perspective deals with consciousness. Although one of the most ambitious pursuits of scientific knowledge is the Human Genome Project, there exists an equally ambitious (even if less well known) human consciousness project. The psychological perspective as revealed by the consciousness project is summarizing millennia of knowledge about the human mind, the subjective human experience, consciousness, the domain of the unconscious, and the farther reaches of human nature (be they existential or spiritual). For more on the human consciousness project go tohttp://www.nourfoundation.com/events/Beyond-the-Mind-Body-Problem/The-Human-Consciousness-Project.xhtml. This knowledge is different from knowledge generated by the medical model perspective, but is no less important for mental health professionals who deal with the whole person. The subjective knowledge about oneself that counseling, psychotherapy, or meditation explore is different from the type of knowledge that science produces to tell us about how nerve cells fire in our brain. It is truly odd that although psychotropic medications are actually supposed to modify experienced consciousness, very few books on the topic actually address that and instead prefer just to discuss how drug molecules bind to neuronal receptors.Suppose, for example, that you experience an insight about yourself that leads to more effective ways of living. For the sake of the example, assume the insight is that you fear emotionally depending on others, so you tend to push them away and isolate yourself. When you experience this insight, certainly nerve cells will fire in your brain, but no one can prove the cells are “causing” the insight—in some cases they accompany it and in others they fire slightly before your conscious knowledge of the insight. Further, others cannot learn about the insight by reading a PET scan of your brain taken when you had the insight. You must truthfully share the insight in order for others to learn about it—no physical measurement of any type (brain cells firing, heart rate, blood pressure, and so forth) will reveal the insight—you must share it. This is an important type of knowledge of the sort commonly shared and explored in counseling sessions.The psychological perspective also includes people’s unconscious life experience. The many tools we use to explore the psychological perspective include introspection, dialogue about that introspection, interpreting dialogue, and sharing our interpretation to assess its accuracy. Although we can only be aware of those things that are conscious, by definition, the tools of the psychological perspective can help clients bring to awaRenéss things that were previously unconscious. As Wilber (2003) noted, psychotherapy is always about increasing awaRenéss and this increase in awaRenéss is experienced through the psychological perspective. These tools are familiar to anyone trained in the mental health professions, but it is amazing how easily we forget their importance.The Cultural PerspectiveA third perspective or type of truth concerns how people should treat one another as well as the beliefs and worldviews people may share. These shared beliefs constitute aspects of culture. Culture, ways of living that groups of humans transmit from one generation to another, includes the shared beliefs and worldviews that different groups develop to understand the world and their place in it. Because shared worldviews are so important to culture, we refer to this third perspective as thecultural perspective. The wordculturemay refer to a subgroup of people who share similar genetic and social histories, as in “African-American culture” or a subgroup that comes about for other reasons, such as a business or industry, as in the culture of a pharmaceutical company. Again, no number of PET or MRI scans of brains can show what worldview a person holds, which ways of relating or worldviews are better than others, or whether a person prefers to be “in time” or “on time.” As Wilber (1995) puts it, scientific knowledge can never tell us why compassion is better than murder, why social service is better than genocide. Michael Polanyi (1958) also articulated this insight. Polanyi was a Nobel Prize–winning chemist who realized during the communist revolutions in Europe that the revolutionaries were trying to build a culture and a society on scientific principles (the Lenin-Trotsky five-year plan) and that those principles were the wrong tools for the task. Polanyi understood that the tools of science could never help these revolutionaries build a culture or a society worth living in. History has validated his judgment. Although the design of the Soviet Union tried to account for and control all the measurable aspects of society, it severely underestimated the cultural/ethnic differences that, since its dissolution, have erupted between former member nations. Scientific truth can tell us which psychotropic medication has the greatest probability of easing a client’s suffering. But the scientific truth and the medication cannot erase nonbiological sources of suffering nor address what this suffering means to the client. For example, if the client shares a worldview that is highly suspicious of taking psychotropic medication, the client is unlikely to comply with the prescription.The Social PerspectiveA fourth type of truth, which concerns the structure and impact of social institutions, we call thesocial perspective. Social institutions are based in shared beliefs, policies, and laws that affect people in observable, measurable ways. Whereas the medical model perspective deals with measurable, observable data about individuals, the social perspective deals with measurable, observable data about groups and particularly institutions. One good example in psychopharmacology is the ongoing debate about whether a person can and should be medicated against his or her will (Gelman, 1999). Although the legal system is ideally based on the public’s shared understanding of how we need to be regulated with laws, laws prohibiting or permitting forced pharmacological treatment have profound impact on individuals. Besides the legal institutions of our society, other institutions relevant to psychopharmacology include the government (e.g., the Food and Drug Administration, the Drug Enforcement Agency) and the pharmaceutical industry in general. Issues such as whether people in the United States should be able to import medications from Canada are the domain of the social perspective. (Again, imagine the absurdity of trying to resolve this import question through the medical model perspective.)Most books on psychopharmacology focus on scientific or medical model perspectives of what medications seem to do, how they correlate with symptom relief, how much of the medication is needed, and so on. Although we cover these issues in detail, we also discuss the other perspectives that are pertinent to mental health professionals. For example, what does it mean to a client to take a psychotropic medication (psychological perspective)? What does it mean that a significant number of children in this society are referred for medication instead of for counseling (social perspective)? How should we interpret and interact with a family that believes psychotropic medication is spiritually damaging (cultural perspective)? It is time for humanity to integrate the various types of knowledge people have access to, and a study of psycho-pharmacology can benefit by such integration.We have mentioned the power of the pharmaceutical industry particularly in the United States. Like all power it can be used well or misused. One of the most striking things since the publication of the first edition of this book is the increase in lawsuits prosecuting pharmaceutical companies for illegal practices related to psychotropic medication. Some examples:•In 2011, Massachusetts filed a lawsuit against Janssen for “deceptive” marketing of the antipsychotic resperidone (Mental Health Weekly, 2011) and settled for $158 million.•Since 2004, the United States has collected nearly $8 billion from fraud enforcement actions against pharmaceutical companies for illegally promoting drugs for off-label uses (Avorn & Kesselheim, 2011).•In 2009, Eli Lilly Company pled guilty to illegal marketing of the antipsychotic olanzapine and paid a $1.42 billion fine (Associated Press, 2009).•In 2010, AstraZeneca was fined $520 million for illegal marketing of the antipsychotic quetiapine (Wilson, 2010).What seems to be happening is that the culture of the pharmaceutical industry is being more closely monitored by government agencies due to a history of ethically questionable actions. This definitely affects clinicians and clients. For example, what if one of your clients was taking a drug that is not FDA approved for a serious disorder like Bipolar I Disorder and that has no documented efficacy? Certainly the client’s welfare is at stake and this is where clinicians advocating for clients and maintaining healthy relationships with prescribing professionals is important.PSYCHOPHARMACOLOGY AND MAGICAL THINKINGR. Stivers, in his bookTechnology as Magic(2001) suggests that as different technologies “disenchant” our sense of the world, people may respond with magical thinking by endowing those technologies with magical attributes. “Today our expectations for technology are magical” (p. 7). You can see this change particularly in psychopharmacology. We have had clients who thought that if they took antidepressant medication prescribed for their symptoms it would (almost magically) erase all suffering from their lives. We agree with Stivers that this society has almost magical expectations of pharmaceutical companies, their products, and the medical professionals who prescribe those products. One practice tied to this expectation is what we call “word magic.”“Word magic” is the use of words in such a way so as to create the illusion of certainty where certainty does not exist. Word magic is used to increase one’s control over the world (and other people), to artificially reduce the complexity of reality, and to help one deal with the insecurity experienced in the face of complexity. Particularly in the service of control, word magic can be used to trigger strong emotions in a reader or listener for the purpose of increasing the speaker’s own power. Former U.S. Attorney General A. Mitchell Palmer and Senator Joseph McCarthy engaged in word magic, wielding the key term “communist” to increase their political power during “red scares” in the early- and mid-20th century. The same type of word magic was used in the witch hunts, in the Inquisition, and is still being used in thecurrent “war on drugs” (which is really a war on drug users) in the United States (revisited inChapter Ten).How does this relate to psychopharmacology? When various professionals, groups, or companies use words to convey pharmacological certainty where little certainty exists, they are engaging in word magic and in some cases trying to increase their own power. An example of this is the flawed idea that mental illness is caused by a chemical imbalance in the brain. As noted this “hypothesis” has been falsified multiple times. This can result in what Charles Tart (1997) refers to as scientism: “a dogmatic, psychological hardening of materialistic belief systems with emotional attachments, rather than authentic science” (p. 22). Frequently this hardening of belief systems with emotional attachments takes the form of proclaiming something to be much simpler than it is in reality. An example is when pharmaceutical companies, in ads for antidepressants, state, “Depression is a serious medical disease.” The payoff for pharmaceutical companies in framing depression this way is that if the general public thinks of depression first and foremost as a medical disease, their first response if feeling depressed will be to go to a medical doctor for a prescription rather than to a mental health professional for counseling. As we will show, depression is an overdetermined set of symptoms that may be biological, psychological, or spiritual in etiology. Just because depression is described in theICD-10(the diagnostic manual for physicians) does not mean it is a medical disease in the same sense that influenza is a disease. Tart goes on to explain that we are conditioned to assume people in lab coats are dealing with certainty and that sometimes people in lab coats perpetuate that misunderstanding.MOVING ON: WHAT WE KNOW, WHAT WE DO NOT KNOWTo avoid falling into word magic, people must be willing to admit what they do not know. Studying the mind and brain moves us all to the knowledge frontier of the 21st century. Consider this: Despite considerable success in developing medications that ease the symptoms of mental and emotional disorders, scientists have little understanding of how most of these medications work. Researchers are learning more about how psychotropic agents act on the brain and body (pharmacodynamics) and how the body disposes of them (pharmacokinetics), but scientists still know very little about why certain drugs decrease certain symptoms and contribute to emotional and behavioral changes. Even more interesting (although less publicized) is that in a great number of studies (and with particular symptoms like depression), as many participants respond to placebos as respond to the actual medications being investigated (Fisher & Greenberg, 1997; Khan, Leventhal, Khan, & Brown, 2002). There are many unanswered questions about the brain, the mind, and the relationship between the two. All together now: “Reality is complex, and complexity is our friend.”An example of this complexity is the case of Louise. Throughout the book, we provide cases that illustrate good responses to medications, treatment-resistant symptoms, side effects, client psychological issues related to medications, and cultural and social considerations. The cases illustrate the complementary types of truths we have summarized as the medical model, psychological, cultural, and social. Although it would be much simpler only to use cases where clients have symptoms, take medications, then get better, this has seldom been our experience. Lawrence’s case illustrates many of the perspectives we have introduced in this chapter. It does not lend itself to a single interpretation that relies solely on one perspective. Read the case, and consider the questions following it.The Case of LawrenceLawrence is a 35-year-old lawyer who anguishes with a very poor self-image, terrible anxiety, depression, and lability of mood. He is the oldest of three and his mother left the family permanently when he was five. At that time, his father expected him to be the little man of the house and take care of his younger sisters. Lawrence remembers that he always complained to his father that he didn’t feelright, not like the other boys. His father would always reply with the same phrase, “Just move on, son.” Lawrence always believed that no one got him, not even his new stepmom. Both at home and in school he was a loner. He was very bright and got more than acceptable grades. He grew very anxious whenever he had to interact with others. His father had no patience for his isolation. Lawrence gradually developed what seemed to be a social phobia.From an intrapsychic perspective, this client suffered a serious loss of the mothering one at a critical time in development. Just as he began to enter the latency age of child development, he loses his primary relationship with whom he can share insights and changes that he is experiencing. This aspect of his development was delayed or foreclosed while his father expected him to accelerate his development to an advanced stage of caretaker of his sisters. In both roles he became very passive. By the time he reached high school he was in a suicidal depression and had to be hospitalized for attempting suicide. Each day of his life was a burden. The attending physicians at the hospital tried to get him to take an antidepressant. He refused.Lawrence graduated from college, served in the army, and married. Eventually, he attended law school with very little alteration of his mood or self-efficacy. He failed the law boards and his wife threatened to divorce him if he did not pass them the second time. He was distraught and angry. He felt betrayed by his wife who had almost forced him to attend law school. He sought out therapy and consultation with a psychiatrist. The therapist recommended twice-a-week psychotherapy and the psychiatrist put him on 100 mg of sertraline (brand name Zoloft). Lawrence tried the sertraline for three months and indicated that he felt no improvement. The psychiatrist added 250 mg of bupropion (brand name Wellbutrin) to be taken along with the sertraline. Lawrence expressed his concern about being over medicated, but the psychiatrist encouraged him to try both medications.After four months, Lawrence spoke to both his therapist and psychiatrist that he believed the medications were not really helping him. After much consultation and discussion with Lawrence, the psychiatrist decided to titrate him off the buproprion and to add 2 mg of aripiprazole (brand name Abilify a newer antipsychotic used at very low doses in the treatment of depression). Within a week, Lawrence was unable to sleep, was very agitated, and could not focus on his work. The psychiatrist, although puzzled, was not totally baffled by this development in Lawrence. He expanded his clinical interview, consulted in-depth with the therapist, and concluded that Lawrence had been masking a bipolar presentation with some moderate drinking. He started Lawrence on a course of lithobid (Lithium) after discontinuing his other medications. This course of treatment served Lawrence well for several years and he periodically had his blood levels checked for lithium poisoning. The course of pharmacological treatment that Lawrence received is far more the norm for the patient of 2013.THE MIND-BRAIN PROBLEMIf you were on a game show and the host asked you (for $1000) to clearly define mind, brain, and the difference between the two, how would you answer? How you answer is basically how you conceptualize the mind–brain problem. The mind– brain problem is an old philosophical issue that addresses whether or not the mind and brain are distinct entities and what their relationship is. Scientific knowledge of both the mind and the brain is incomplete. No one knows what the mind is, where it comes from, or how it interacts with the brain (Dossey, 2001). However, numerous scholars have noted that even if there were complete knowledge of the mind and brain, the problem might still be unsolvable (Koch, 2012). Consider being asked to define “the mind.” At first glance this might seem a simple task for a mental health counselor or a student training in one of the mental health professions. In fact, it is a rather vexing question with a multitude of answers depending on your theoretical orientation. As much as many hate to admit it, to “define” what “mind” means first requires a leap of faith in the theory or theories you believe most accurately reflect the reality ofwhat the mind is. To say you adhere to a particular theory of the mind–brain problem is fine; to claim a particular theory is ultimately true at this point in history is scientism, not science. Generally, the mind–brain problem has been explored through two hypotheses, the epiphenomenon hypothesis and the dual-substance hypothesis, discussed as follows.The Epiphenomenon HypothesisThe first hypothesis is called theepiphenomenonhypothesis (sometimes called the “side effect” hypothesis—the mind is a side effect of the brain). The theory underlying this is what might be calledradical materialism. The basis of radical materialism is that all things, including the mind, derive from other things that can be objectively observed and measured. This hypothesis states that the mind derives from the brain. In other words, the mind is an epiphenomenon of the brain. In a sense, this theory claims that your mind, including your sense of self, is a “side effect” of having a developed brain. The 19th-century biologist Thomas Huxley (known as “Darwin’s Bulldog” for his fervent support of Darwin’s theory of evolution) popularized this hypothesis. More recently Damasio (2000), Dennett (1991), and Churchland (1995, 1999) have set forth varieties of the theory. Sometimes the theory is not stated outright but implied, as if this were the only acceptable theory on mind and brain. Richard Thompson (2000) gave one example when he wrote, “What is consciousness and how does it arise from the brain?” (p. 481). His implication that it does arise from the brain is a theoretical assumption, not an indisputable fact even though he presents it as such. This is another example of word magic—using words to create an illusion of certainty where there is none.Advocates of the epiphenomenon hypothesis support it by first noting a brain structure responsible for a particular function (such as the relationship of Broca’s area to speech, for example). Next they point out that, for example, if Broca’s area is damaged, speech is impaired. The reasoning is that one’s sense of self (one’s mind) is a consequence of brain functioning and if those parts of the brain responsible for the sense of self are damaged, the sense of self is either impaired or vanishes, just as speech becomes impaired if Broca’s area is damaged.Perhaps the most time-worn example used to support the epiphenomenon hypothesis is the 19th-century case of Phineas Gage. Gage was a railroad construction worker who had a tamping iron driven through his skull as the result of an explosion. Although he miraculously survived the accident, the story used to be that his personality became so altered that those who knew him say Gage was a different person after the accident. Damasio (1995) hypothesized that from a materialist perspective Gage, the person, had changed because the areas of his brain that maintained and expressed personality had changed when damaged in the accident. Of course, as in most things, there is now a difference of opinion on Gage. Kean (2014) wrote that descriptions of Gage’s personality change are greatly exaggerated. In fact, he noted that historical documents show that Gage went to South America and worked as a stage coach driver. Even if the stories about his drinking and aggression after the accident are true, how much of that may have been related to pain or depression (the psychological perspective)?Our sense of self is somewhat more complicated than other functions that are traced to specific brain areas, so researchers do not yet know exactly which areas, and the relationships between them, result in the sense of self. Damasio (2010) and others have begun to tackle this problem, but science is far from an explanation. Thus to accept the radical materialist position is a statement of faith that neuroscientists will be able to completely map out the brain and its functions (and that they are correct in thinking such knowledge would resolve the mind–brain problem).As you can imagine, those who adhere to the medical model of mental and emotional disorders often support the epiphenomenon hypothesis. This model is the basis of allopathic medicine. Allopathic medicine (as opposed to homeopathic or osteopathic) is the branch of medicine that adheres to the philosophy that to treat or cure a diseaseprocess, you introduce an agent (such as a drug) that acts in a manner opposite to the disease process you are trying to treat or cure. Although it is often assumed that if scientists know a disease process they also know its etiology (cause), this is far from true. Thus, there is no foundation for the allopathic assumption that identifying a disease process (depressive symptoms for example) and decreasing or stopping that process means that the process had a physical origin. Strict adherence to the medical model leads to unfounded assumptions that all mental or emotional disorders derive from faulty functioning in the brain or nervous system. Many follow this strict adherence despite strong evidence that the mind (at least the thought processes and emotions of the mind) influences the body as much as any organ like the brain and particularly disorders like depression and anxiety. Although we would agree that severe mental disorders like Schizophrenia will almost certainly turn out to be primarily physiological in their etiology, others like depression are overdetermined (meaning there are many ways one may develop depression).The Dual-Substance HypothesisThe dual-substance hypothesis is often dated back to the philosopher René Descartes who lived in the early 17th century, although it certainly predates Descartes, because it exists to some extent in both Hindu and Buddhist philosophy. Descartes proposed both that a divine being exists and that this divine being created thinking things (res cogitans) and material things (such as bodies) that extend into the material realm (res extensa). He thought thinking things do not actually exist in time and space and cannot be externally observed. The extended beings do exist in time and space and can be externally observed. Although Gabbard (2001) believes that substance dualism has fallen out of favor, there is still ample support for variations on the hypothesis. Most variations equate “mind” with “consciousness.”Those holding a spiritual worldview often accept the dual-substance argument (in various formulations). Such a worldview may endorse a belief in a God or Divinity of some sort and possibly some notion of an eternal soul. This is not necessary, however, because the Buddhist view, for example, refers to different types of consciousness. One such type is a nonmaterial, ever-present “subtle consciousness” that we are thought to be most in touch with in deep sleep, advanced meditation, sneezing, and orgasms (think about that next time you sneeze!). From the Tibetan Buddhist perspective, epiphenomenalism and radical materialism fall into the trap of reifying physical phenomena (Descartes’sres extensa) and denying the existence of mental phenomena (Descartes’sres cogitans) (Wallace, 1999). From this perspective, to say that consciousness depends on the brain for existence is akin to saying that food depends on a stomach for existence. Psychologist Dean Radin (1997) wrote, “The average neuron consists of about 80 percent water and about 100,000 molecules. The brain contains about 10 billion cells, hence about 1015molecules. Each nerve cell in the brain receives an average of 10,000 connections from other brain cells, and the molecules within each cell are renewed about 10,000 times in a lifetime” (p. 259). Radin then asked why, despite this continuous change, the patterns of our sense of self remain stable even though the physical material supporting that sense of self is in constant flux. The body you have while reading this (including your brain) is not at all the same body you had three years ago, but your sense of self is.In addition to these two perspectives on the mind–brain problem, there are also variations such as interactionism (mind and brain are different but mutually causal) and parallelism (mind and brain are totally separate and do not communicate).The mind–brain problem is an important context for the study of psychopharmacology. If this context is ignored, it is far easier to ignore things, such as the placebo effect, that hold important truths, as yet untapped, that may contribute to our knowledge of healing the symptoms of mental/emotional disorders. Ignoring the mind–brain problem also makes it easier to commit category errors and support themwith word magic (such as asserting that all depression is caused by a “chemical imbalance”).THE LAYOUT OF THIS BOOKPart OneThe first part of this book covers introductory material on the basic principles of psychopharmacology derived from the medical model as well as material representing the different truths or perspectives that complement the medical model. The information inChapter Twofocuses on pharmacokinetics: how the body acts on drugs.Chapter Threefocuses on pharmacodynamics: how drugs act on the body.Chapter Fouris an overview of the nervous system and tells the story of neurotransmission. The story of neurotransmission is the story of how brain cells (neurons) communicate both electrically and chemically. If you know this story, you have a general understanding of how psychotropic medications are designed and what they are supposed to do. The story of neurotransmission gives you a sense of the complexity of neurotransmission and a sense of how much people have yet to learn about it. By understanding the story of neurotransmission you will also be able to conceptualize what we currently know about mechanisms of action of psychotropic medications and about strategies pharmaceutical companies use to develop newer drugs.Chapter Fivegives an overview of relevant issues from the psychological perspective—the subjective sense of our experience of life. Psychological issues also include interpersonal issues relevant to mental health practitioners working with clients and other professionals. These issues include how to talk with clients about medication and compliance, how to approach collaboration with prescribing professionals, and how to process particular issues in supervision. InChapter Six, the last chapter inPart One, we cover important social and cultural issues. We give an overview of cultural, racial, and gender differences regarding responses to psychotropic medication and then discuss the relevance of powerful institutions such as the pharmaceutical industry and the Food and Drug Administration.Part TwoThe second part of the book contains four chapters covering classes of commonly prescribed psychotropic drugs used to treat depression, anxiety, psychosis, mood instability, and a host of other conditions. Each chapter includes some history on the discovery and use of each category of drugs. This history provides the context that informs the four perspectives we comment on in each chapter. In addition to the history, we present medical model theories of how the drugs work and cover common drugs in each category including their side effects. Then, in each chapter, we include relevant material from the psychological, cultural, and social perspectives. Note that a medication approved by the FDA for some use has both a generic name and a brand name (or brand names). For example, Prozac is a brand name for a drug, the generic name for which isfluoxetine. Throughout the book when we refer to a drug in an example we try to provide the reader with both generic and brand names. ThePDR, thePhysicians’ Desk Reference, is the standard reference book on drug names, both generic names and brands. It is available both at the reference desk of most public libraries and online.Part ThreePart Threeof the book, titled “Newer Issues,” addresses psychotropic medications for children (including stimulant medications), the elderly and psychotropic medication, an update on herbaceuticals, a chapter on drug replacement therapy and the conclusion. The chapters in this part differ from those inPart Twoin that these are newer areas and often have been the subject of fewer research studies. Many of the agents discussed inPart Twoand used with adults are still being investigated for efficacy with children. Although scientists have done a great deal of research on the medical model of how stimulants affect children, they have only just begun to deal with which childrenare really good candidates for stimulant therapy and what the medicating of young children means for this society. Note that each chapter contains study questions and exercises for the reader.CHAPTER TWOIntroduction to the Nervous System, Neurons, and PharmacodynamicsINTRODUCTIONThis chapter has six sections. The first introduces the central and peripheral nervous systems. The second takes a closer look at the central nervous system. The third section introduces glial cells and neurons. The fourth section introduces neurotransmitters. The fifth tells the story of neurotransmission and the sixth discusses pharmacodynamics or how drugs act on the brain.SECTION ONE: AN OVERVIEW OF PHYSIOLOGY RELEVANT TO PSYCHOPHARMACOLOGYLearning Objectives•Know the basic parts of the central nervous system.•Know the divisions of the peripheral nervous system.•Understand that side effects can impact the central and peripheral nervous systems.In this chapter, we provide an overview of the central nervous system, the brain, the brain’s individual cells (calledneurons) andpharmacodynamics(how drugs act on your body). This material has been the focus of most psychopharmacology texts, but remember, it is only part of the story—an important part that discloses truth—but not the whole truth.In studying this material, some students become anxious, thinking, “I don’t really have any background in biology or physiology.” Relax. If “hard science” doesn’t come naturally to you, think of the brain and the nervous systems as miraculous works of art that you can experience even if you cannot fully understand them. Set aside quiet study time to read this material. If it is new to you, don’t expect to grasp it reading in 20-minute intervals or in a distracting environment. Approach this chapter as a “brain appreciation” tour. Remembering our mantra and the fact that the best “hard science” minds in the world are really just starting to understand the brain, sit back with a warm drink and join us for this tour through the most complex organ known to human beings.A FEW BASICSWe start with a sketch of thecentralandperipheral nervous systems.Figure 2.1illustrates key parts in both systems. Although we focus on central nervous system effects from various medications, it is important to understand some basics of the peripheral nervous system, because many drugs haveside effectson this system. Much of the information in this section is drawn from Advokat, Comaty and Julien (2014), Bloom, Nelson, and Lazerson (2005), Carlson (2012), and Thompson (2000). Readers interested in full expositions of the brain and central nervous system are referred to their work.The central nervous system includes the brain and spinal cord. The peripheral nervous system (the nervous system outside the brain and spinal cord) is divided into thesomaticandautonomic(or visceral)nervous systems. The somatic nervous system connects with sense receptors and skeletal muscles while the autonomic nervous system controls involuntary functions related to the glands, smooth muscles, heart, and viscera. This is important, because the goal forpsychotropicdrug compounds is to get them into the central nervous system. Remember that “psychotropic” means acting on or moving toward the mind, but because we lack a clear understanding of the relationship between mind and brain (as discussed inChapter One) the medical model perspective assumes most psychotropic medications have to reach the brain. Note that there is also ample evidence that what we call “mind” may have correlates in other parts of the body, such as the bacterial signature we each carry in the gut which may also affect mental disorders (Bested, Logan, & Selhub, 2013; Forsythe, Kunze, & Bienenstock, 2012; Rodriguez, 2013; Stafford, 2012).FIGURE 2.1Basic Overview of Human Nervous SystemsThe nerves in your body and head that send information to and from the central nervous system are peripheral nerves. As you can see inFigure 2.1, the peripheral nervous system consists of the somatic and autonomic nervous systems. The somatic nervous system consists of peripheral nerves (nerves outside the central nervous system) that connect with sense receptors (receptors for vision, taste, and so on) and with skeletal muscles. The somatic nervous system regulates voluntary activity and relays information from the sensory organs to the central nervous system and from the central nervous system to the skeletal muscles. Thus, when you see a pint of Haagen-Dazs ice cream, the somatic nervous system relays the visual stimulus to the central nervous system where you decide to reach for the pint (and a spoon). Next the signal for reaching for the ice cream is relayed back to the skeletal muscles, and that signal brings a creamy delight within your reach.The autonomic (visceral) nervous system regulates activities that are primarily involuntary. For example, once you have enjoyed your ice cream, the autonomic nervous system is correlated with activities such as digesting, so you can just bask in the afterglow of a good “sugar high.” The autonomic nervous system is further subdivided into the sympathetic nervous system (active during arousal such as fight, flight, or freeze responses) and the parasympathetic nervous system (active during conservation of energy). Activation of the sympathetic nervous system mobilizes your bodily resources and prepares you to expend energy. For example, if you left the Haagen-Dazs on the counter and your dog spied it just before you reached for it, your sympathetic nervous system would help you spring into action, thwarting Fido and capturing your prize. The activation of the parasympathetic nervous system deactivates organs that the sympathetic nervous system activated. Once the ice cream is safe in your grasp, your parasympathetic nervous system returns your body tohomeostasisso you can settle down.A ready example of how a drug affects the peripheral nervous system is the popular antidepressant fluoxetine/Prozac (when referencing drugs in a chapter we will use the generic name, a forwardslash (“/”) and then the brand name). Physicians often recommend that patients take fluoxetine/Prozac with food. This is because a common side effect of fluoxetine/Prozac (and most similar antidepressants) is nausea. This nausea occurs because the fluoxetine/Prozac affects serotonin receptors, and the peripheral nervous system in our digestive tracts is rich in these receptors. Because the drug must pass through these peripheral nervous system structures to get into the bloodstream and eventually the central nervous system, along the way any receptors to which the drug binds are affected. This also returns us to the interesting point about the “mind” being linked with the “gut.” Could antidepressants acting on these gut receptors be causing more than just “side effects”? Even if the mind did turn out to be totally generated by the brain (the epiphenomenon hypothesis inChapter One), what if the “brain” we are referring to includes the entire nervous system? Until researchers can secure funding to think beyond the limits of the current models, such questions remain unexplored.Review Questions•What are the two general parts of the central nervous system?•What are the functions of the somatic and autonomic nervous systems?•Why can drugs cause side effects in areas like the gut?SECTION TWO: EXPLORING THE CENTRAL NERVOUS SYSTEMLearning Objectives•Be able to generally describe functions related to the brain stem, midbrain, and neocortex.•Know what sorts of mental health symptoms may be directly related to the functioning of the limbic system.•Understand the structural relationship between different parts of the brain.As noted, the central nervous system consists of the brain and the spinal cord. The brain has three general “layers” that developed through evolution, commonly called thebrain stemorreptilian brain, the midbrain ormammalian brain(which is technically part of the brain stem), and theneocortex. There is also the cerebellum (Latin for “little brain”) that controls motor functions and posture. The brain has structures in and across these layers that we have correlated with particular functions. There are several ways to classify brain structures. We have followed the systems used by Advokat et al. (2014) and Carlson (2012), because these authors are highly respected in the field. Note that although some names of the brain structures may seem unfamiliar, they are usually Latin or Greek words for rather mundane objects and we will translate them as we go.Exploring the Brain StemThe brain stem includes structures that function to keep us alive.Figure 2.2illustrates the structures of the brain stem and midbrain. When drugs interfere with the function of these structures, the results can be life threatening. For example, when a person drinks so much alcohol that it inhibits the neurons in these structures, the result can be coma and death.The medulla oblongata is described as “the continuation of the spinal cord in the brain” (Thompson, 2000, p. 14) and controls breathing, heart rate, blood pressure, skeletal muscle tone, and digestion. This small, complex structure forms many connecting links between brain and spinal cord. Shaped like a pyramid, it is about an inch long and less than an inch across at its widest area. Its name comes from the Latin for “long marrow.” The structure is so dense in neurons that the tissue looks dark, like bone marrow. Sometimes it is simply called the “medulla.”There is an important cluster of neurons in the brain stem called thelocus coeruleus(pronouncedsaroolee us), from the Latin for “blue disc”; the cluster of neurons has a blue appearance. This structure consists of neurons that release norepinephrine and appear to help the person set priorities on incoming signals and decide where to place attention. Because of this link with attention, the role of the locus coeruleus is being investigated for links to the symptoms of attention deficit hyperactivity disorder (ADHD).FIGURE 2.2The Brain Stem and MidbrainThe pons (from the Latin for “bridge”) connects the medulla oblongata and the midbrain. It also connects the two halves of the cerebellum. The pons extends into the reticular formation (part of the midbrain) and governs alertness, waking, sleeping, muscle tone, and some reflexes. The reticular formation has a netlike appearance (from the Latinreticular, “netlike”). The brain stem also includes the raphe nuclei (meaning “nerve cells forming a seam”). The raphe nuclei contain serotonin neurons and are thought to trigger slow-wave sleep. You can imagine the importance of understanding this if a client is going to take a drug that radically increases levels of serotonin in the brain. By increasing serotonin in this area, the drug is also going to cause sleepiness and possibly disrupt the sleep cycle, because serotonin is involved in sleep functions in the brain.Exploring the MidbrainThe midbrain is also labeledmesencephalon(Greek for “midbrain”) and is a continuation of the brain stem (seeFigure 2.2). It merges into the thalamus and hypothalamus and encompasses what Advokat et al. (2014) call the “subthalamus.” The subthalamus, combined with the basal ganglia, constitutes one of our motor systems called theextrapyramidal motor system. All information that passes between the brain and the spinal cord travels through the midbrain. As mentioned, the reticular formation is an interconnected network of neurons that extends from the spinal cord into the midbrain. These neurons are implicated in sleep, arousal, and a number of vital functions. The medulla, pons, and midbrain are thought to have developed early in human evolution (thus the common name “reptilian brain”).The CerebellumThe cerebellum (from the Latin, meaning “little brain”) looks like a little brain attached onto the larger cerebrum (illustrated inFigure 2.3). The cerebellum lies over the pons and is crucial to things such as balance and smooth, coordinated movement. It has connections with the vestibular system (the balance system located in the inner ear), the auditory, and the visual systems. The cerebellum, the subthalamus, and the basal ganglia make up theextrapyramidal system, which helps coordinate movement, including initiation, smoothness, and termination of movement. If people take a medication that interferes with the functioning of the extrapyramidal system, they will likely suffer from involuntary movements calledextrapyramidal side effects. We discuss these in detail in our treatment of antipsychotic medications.Exploring the Diencephalon“Encephalon” is a Greek word that simply means “brain.” “Di” means “between,” so the diencephalon is between the telencephalon and the brain stem. There are several important structures in this brain area. The thalamus, a large group of nerve cells, acts as the final relay area for the major sensory systems that project to the cerebral cortex: the visual, auditory, and somatic sensory systems (Thompson, 2000). Oddly enough, the translation of the Latin wordthalamusis “bedroom” or “receptacle.” Although “receptacle” means basically “final relay area,” we have yet to figure out how “bedroom” fit in for the ancient translators, but feel free to use your imagination.FIGURE 2.3A Sagittal Section Through the Human BrainThe hypothalamus (“below the thalamus”) is a collection of cells that lie above the pituitary gland and immediately in front of the midbrain. The hypothalamus controls the autonomic nervous system and endocrine system and maintains the body’s homeostasis (internal state). It also regulates temperature, fluids, metabolism, appetite for specific nutrients, as well as what are called the “four Fs” (Fighting, Feeding, Fleeing, and Mating—again, use your imagination). Hormones secreted by the hypothalamus control the pituitary gland. Part of the wide-ranging influence of the hypothalamus is related to its control over the pituitary gland. Together, they act as a “master control system.” “The hormones they release act on the otherendocrine glandssuch as the thyroid, adrenal, and pituitary glands that secrete certain substances, particularly hormones, directly into the blood. The hormones released by the endocrine glands then act back on the pituitary gland and hypothalamus to regulate their activity, an example of feedback control” (Thompson, 2000, p. 17). The hypothalamus is also located near and has influence over what Olds and Milner (1954) dubbed the brain’spleasure centers.Exploring the Limbic SystemThe limbic system is a series of brain structures that help us attach emotional meaning to sensory stimulation. In some systems of classification the limbic system is associated with the diencephalon, and in others it is associated with the telencephalon. The limbic system includes the amygdala (Latin for “almond,” which it resembles), the septum (Latin for “dividing wall” or “enclosure”), the hippocampus (Latin for “seahorse” and based on resemblance), and portions of the thalamus. Bear in mind that many of the structures we are discussing are actually two—one on each side of the brain so technically you have two “amygdalae” but for sake of ease we refer to these in the singular. The amygdala integrates and directs emotional behavior, attaches emotional significance to what the senses signal, and mediates defensive aggressive behavior. Damage here can produceKluver-Bucy syndrome, which is characterized by diminished fear and aggression as well as amnesia and hyper sexuality. The septum inhibits emotionality, as evidenced by the fact that lesions in the septum produce septal rage syndrome. In this syndrome, damage to the septum leads to uninhibited emotional expression, particularly the expression of anger and aggression. The septum is also part of the pleasure centers of the brain. The hippocampus is a curved ridge in the limbic system, involved in moving signals from short-term memory to long-term memory.Exploring the TelencephalonThetelencephalonconsists of the right and left halves of the cerebrum (telis a variation of the Greektele, meaning “end” or “complete,” so the translation is “end of the brain” or “completion of the brain”). The outer portion of the cerebrum is the cerebral cortex. This is the brain’s outermost layer, the image you are probably familiar with from pictures of the human brain. This cortex is divided into four lobes (roundish projections) by sulci (deep grooves in the surface). The four lobes are named for the bones of the skull covering them (seeFigure 2.3) (Carlson, 2012). This part of the brain is correlated with the functions related to self-awareness or sentience that make humans unique in the animal kingdom. The tissue in the lobes can generally be mapped according to function, although in many cases, if an area is damaged another part of the brain may pick up that function. For most functions, their expression is contralateral (“opposite-sided”), meaning that an area on the right side of the brain controls something on the left side of the body. Next we summarize the four main lobes and some of their general functions.The frontal lobes of the cerebral cortex are generally involved in motor behavior, expressive language, concentration, orientation (time, place, and person) thinking, and reasoning. These lobes contain the pyramidal system that is involved in fine, intricate movements. The left frontal lobe containsBroca’s area, which is involved in speech production, and damage to this area can produce the experience ofexpressiveaphasia (a self-conscious deficit in the ability to articulate or express language). The temporal lobes (located near the areas of your head called the “temples”) are related to receptive language, memory, and emotion. These lobes containWernicke’s area, which is involved in comprehending language. Damage to this area can producereceptiveaphasia. The parietal lobes are located under the skull on the top of your head and contain the primarysomatosensory cortex. This area receives and identifies sensory information from tactile receptors and processes visual and auditory sensations. Damage to the parietal lobes can produce Gertsmann’s syndrome, which includes agraphia (inability to write), acalculia (difficulty with mathematical calculation), and right–left confusion. As you can imagine, researchers are trying to link whatDSM-5calls Specific Learning Disorders to these areas of the brain (e.g., impairment in mathematics is related to problems in the parietal lobe). Finally, the occipital lobes (at the back of your head at the base of the skull) are largely associated with thevisual cortex. Damage to the occipital lobes produces visual agnosia (the inability to recognize familiar objects on sight).Under the cortex lie the smaller areas of the telencephalon (Bloom et al., 2005). The basal ganglialie at the central regions of the cerebral hemispheres and are systems of cellnucleithat effect voluntary movement. They form the primary part of the extrapyramidal motor system (described earlier). Next we focus on the nerve cells in these structures and their function, so that we can begin to explain the mechanisms of action in psychotropic medications.Review Questions•How would you generally describe the functions of the brain stem, midbrain, and neocortex?•What part of the midbrain is likely indicated in anxiety symptoms?•What is the relationship of the cerebral cortex to the cerebrum?SECTION THREE: AN OVERVIEW OF NEURONS AND GLIAL CELLS“Neurons do not define the essence of people, nor do deficiencies in neurotransmitters explain mental disorders” (Kay, 2009, p. 288).Learning Objectives•Be able to discuss how neurons differ from other cells in the body.•Be able to draw a simplistic picture of a neuron and label the soma, nucleus, axon, terminal button, synaptic vesicles, dendrites, and receptors.•Know why the blood-brain barrier is important to designers of psychotropic medications.•Understand our revised science of what glial cells do.The brain weighs about 3 pounds and has a volume of about 3 pints. It contains a lot ofneurons. Accounts vary on to how many neurons the brain contains: for example, Churchland (1995) and Cozolino (2010) estimate about 100 billion while Barlow and Durand (2002) estimated about 140 billion. Most recently Advokat et al. (2014) estimated 90 billion. Perhaps we are best off estimating “many billions of neurons in every human brain” (Thompson, 2000, p. 29) (or as Carl Sagan might have put it, “billions and billions”). As cells, neurons are unique in that they are created before we are born and have the capacity to live as long as we do. Up until the beginning of the 21st century, scientists commonly believed that at birth human beings had all the neurons they were ever going to have. This view is changing, as researchers now confirm that neurogenesis (the growth of new neurons) occurs in adult mammals (Martino, Butti, & Bacigaluppi, 2014; Shors et al., 2001; Van Praag, Christie, Sejnowski, & Gage, 1999) and correlates with the learning of new tasks (Gould, Beylin, Panapat, Reeves, & Shors, 1999).Although all human cells renew themselves, not all cells divide regularly. One reason that neurons may not divide as regularly as other types of cells is that they form essential functional units in brains. As Thompson (2000) pointed out, everything people are or do has correlates in the sequencing of neurons and their interconnections. If neurons had to keep dividing to replace themselves, valuable sequences and interconnections might not form.Although neurogenesis research continues to explore questions about how new neurons form, most knowledge about the correlation of neuronal function concerns the growth of axons and dendrites from existing neurons. This growth (calledarborization) is prolific in the first few years of life. Moreover, you may have heard the saying “Size doesn’t matter,” and this is particularly true of the brain. Whales and dolphins have larger brains than humans, and although these mammals are no slouches intellectually, they do not match the human brain capacity for representational power. Nor do thenumberof neurons matter; it is the number of connections between the neurons that is important.The neurons of the human brain have an enormous representational capacity. By way of analogy, Churchland (1995) compares this capacity to a standard 17-inch television screen. Such a screen has a representational capacity of about 200,000 pixels (a pixel is the smallest element of an image that can beprocessed). To get enough pixels to match the representational power of your brain, you would have had to cover all four sides of the Sears Tower in Chicago with such screens—and you have it all between your ears, as the saying goes. Such is the representational power of the brain.THE BASIC ANATOMY OF A NEURONFigure 2.4is a simplistic rendering of a neuron. Actual neurons vary in length from a few millimeters up to about a meter and may have several thousand synaptic connections with other neurons (Julien, Advokate, & Comaty, 2014). Neurons come in many different types and shapes, but they all have structures similar to the ones in the figure. It is important to learn a simplistic version of a neuron first so that you can learn the story of neurotransmission. Then you can learn how medications interfere with the sequence of events in that story (or in other words how medications change the story of neurotransmission). Once you’ve learned that, you have a basic sense of the mechanisms of drug action. The importance of learning the basic parts of the neuron will become clear as we discuss the mechanisms of action of psychotropic medications. UsingFigure 2.4as your guide, let us begin by discussing the soma or cell body of the neuron. The dark spot on the figure of the soma is the cell nucleus, which contains the genetic material of the cell. The soma contains themitochondria, which are structures that provide energy for the neuron. Extending from the soma in one direction aredendrites, which are structures that receive inputs or messages from other cells through receptors. The receptors are typically pictured as located on the ends of the dendrites but can occur anywhere on the neuron. Receptors are basically chains of proteins that act as communication devices, allowing neurotransmitters (chemical messengers) to bind to them.In our illustration, extending in the other direction from the soma is the axon. Many elements made in the soma (such as enzymes and receptors), as well as the “raw materials” for these elements, are transported up and down the axon. The axon also transmits electrical signals that can cause the cell to “fire.” When a cell “fires,” it releases neurotransmitter molecules from its terminal button. In our illustration at the far end of the axon are the terminal buttons. The terminal buttons contain sacks (calledsynaptic vesicles) of neurotransmitter molecules. When the electrical signal causes the cell to “fire,” these sacks merge with thepermeablemembrane of the terminal button and the neurotransmitters are released into the synaptic cleft or synapse (the space between the terminal button and the neighboring receptors to which the neurotransmitter will bind). Although there is a universe of activity in each cell, this glance at the general components will suffice until later in the chapter, when we discuss neurotransmission in more detail.FIGURE 2.4Components of a Motor NeuronNow, we say that chemical neurotransmission occurs at thesynapses, which Stahl (2000) defines as “specialized sites that connect two neurons” (p. 1). Neurons send synaptic information through firing and releasing neurotransmitter molecules. They receive synaptic information through their receptors. The number of synapses (points of connection between a neuron and neighboring neurons) on each neuron varies from around 5000 on a mammalian motor neuron to some 90,000 on a single Purkinje cell in the cerebral cortex. (This type of cell, named after the Czech physiologist who first charted its function, is related to the contraction of the heart.)When the body is resting, the brain, which accounts for only about 2% of the body’s mass, consumes about 20% of the body’s oxygen. This is a lavish consumption of energy! The brain needs all this energy to maintain ionic gradient essential to receiving and sending information via the synapses. An ionic gradient is a form of potential energy that keeps the chemistry inside a cell different than the chemistry outside the cell so it can be thought of as a charged signal (an electrical charge). You can think of this charge as a rate of change in relation to the distance of the axon. There is a structure on the axon called the axon hillock. It is the last site in the soma or cell body where incoming signaling is summed and if it surpasses a particular threshold, the action potential (charge) is initiated down the axon toward the terminal button. As the electrical charge travels down the axon it may be facilitated by the influx of positively charged ions (e.g., sodium) or inhibited by an influx of negatively charged ions (e.g., chloride). When the action potential is facilitated all the way across the axon to the terminal button the cell fires, or releases, its neurotransmitter. As noted, to carry an electrical charge down an axon, positive ions must flow into the axon. Once the charge is carried down the axon, these positive ions are pumped back out of the cell (this is sometimes referred to as thesodium potassium pump). As you will see, these ionic gradients play the key role in determining whether or not neurons fire. Imagine: A single neuron handles a thousand signals in the space of a second, and it may fire several hundred times a second, so its energy consumption must be lavish.GLIAL CELLSOnce thought to be an energy-saving device, glial cells have turned out to be much more. Myelin (pictured inFigure 2.4) is peculiar to vertebrates, although not all neurons in vertebrates are myelinated. For example, phylogenetically older fibers such as the C-fibers that innervate the skin and carry information about pain are less myelinated. If you have ever been pounding a nail and the hammer slipped, smashing your finger, you may recall having that split-second knowledge that it is going to hurt in a few milliseconds. With more myelin, you wouldn’t have those milliseconds to anticipate the coming pain. Myelin is made of glial cells (particularly Schwann cells and oligodendroglia) but as you proceed up the evolutionary ladder, a particular type of glial cell called astrocytes increase in size and number.1In the 20th century, it was believed that myelin acted like the insulation on electrical wiring. This is one function of myelin. The more myelinated an axon is, the better insulated it is and the faster it can conduct a signal. When you see a person with a disease that degrades the myelin (such as multiple sclerosis), you see that he or she has difficulty moving, because the nerves coordinating the signals for the movement cannot send the electrical signals efficiently.The conduction velocity depends on the diameter and myelination of the axon. A well-myelinated axon in a human motor neuron can conduct an impulse as fast as 130 meters per second (equivalent to approximately 300 miles per hour), whereas an unmyelinated fiber conducts at about 0.5 meters per second (a little over 1 mph). Events in the world of silicon chips happen in the nanosecond (a one-billionth of a second), whereas events in theworld of neurons happen in the millisecond (a one-thousandth of a second). Brain events are quite slow in comparison to computer events, but in complex tasks such as recognition, brains leave computers “in the dust,” because brains accomplish recognition more quickly. In addition, all computers must put information through a central processing unit (CPU) whereas brains have enormous redundancy in the system so that if a signal does not get from point A to point B, the same signal can be sent from point C to point D or from point E to point F. Neurons are plastic and dynamic. Their information-relevant parts grow and shrink. The axons and dendrites are constantly changing, establishing new connections and removing old connections. This “arborization” is an important concept in psychopharmacology, because many drugs exert an influence to change the information-relevant parts of the neurons. Neurogenesis research findings are so new that speculations on the implications for pharmacology have just begun.Myelin is made from a type of cell called a “glial cell.” “Glial” means “glue,” and glial cells form different types of protective barriers (sheaths) around neurons (of which myelin is one). In the late 19th century, when Ramon Santiago Cajal was doing work with neurons, his brother Pedro set forth a theory that glial cells were simply “support cells” for neurons. Cajal accepted his brother’s theory and this led to the “neuron doctrine,” which posited that neurons alone were responsible for our thought and mental processes. Glial cells usually outnumber neurons by a ratio of 10:1 making up 85–90% of the brain. Under the influence of the neuron doctrine, 20th century laypeople came to believe that we only used 10–15% of our brain power (because of course 85–90% of the cells were glial cells).In different parts of the body, glial cells have different names that reflect the person who discovered them or their function. In the peripheral nervous system, Schwann cells perform the myelinating function; in the central nervous system, oligodendrocytes perform the same function. A third glial cell type, astrocytes, function as fences and filters for the blood–brain barrier and more importantly move neurotransmitters, food, and waste around the brain. A fourth type, microglia, function as scavengers cleaning up dead neurons and other disintegrated material (Fields, 2008, 2011). We’ll take another look at the blood–brain barrier shortly.Another important finding about astrocytes is that we learned that they can communicate to themselves with calcium waves. Astrocytes have hundreds of “endfeet” that spread out from their body toward blood vessels, other astrocytes, and neuronal synapses. Calcium released from internal stores can spread from astrocytes to areas hundreds of times larger than the original astrocyte. These calcium waves can also cause neurons to fire (Koob, 2009). This could radically alter our understanding of the electro-chemical processes in the brain. The implications are huge as we add the impact from 85% of the brain’s cells, which previously have been more or less ignored in our efforts to understand the brain. This might be akin to thinking you know football as a game where a team must move the ball 100 yards to score a touchdown. Then you learn that actually it is 350 yards and the ball moves not just because of the teams but also in response to the volume of the crowd and how their cheers bounce off cars in the parking lot. It looks as if taking glial cells into the equation is literally a “whole new ball game.”THE BLOOD-BRAIN BARRIEROver 100 years ago, Paul Ehrlich discovered that if blue dye is injected into an animal’s bloodstream, all the tissues are tinted blueexceptthe brain. You must inject the dye into the brain ventricles to get that tissue to turn blue. Although Ehrlich was working for a dye company on a different project, he thus unwittingly discovered the blood–brain barrier. In most of the body, the cells that form the capillaries are not spaced tightly together, so substances can move from blood plasma to the tissue.In the central nervous system, the capillary cells do not have the same gaps, because they are filledby the astrocytes that make up the blood—brain barrier. This barrier blocks many substances from entering the central nervous system. In some areas, the barrier is weaker than others, to allow specific functions that have developed through evolution. One example of such an area is thearea postrema, which signals vomiting. The barrier is weak here, so toxins in the blood can be detected. Once it detects toxins, the brain triggers the vomiting response to preserve the organism.The blood–brain barrier serves an important survival function by keeping foreign elements such as toxins out of the brain. But what about things such as nutrients? Nutrients such as glucose must be transported through the capillary walls by special proteins. This is very important, because to exert their effects all current psychotropic medications must reach the central nervous system. To do so, they must pass through the blood–brain barrier. The glial cells that make up the blood–brain barrier have a high fat content. The myelination of the brain in infancy is one reason babies need a lot of fat in their diet. We refer to fatty cells as fat soluble (the technical term for this islipophilicitous— another great cocktail party word). Thus, to pass through the blood–brain barrier, a molecule also must be highly fat soluble. Almost all psychotropic medication molecules are fat soluble, with perhaps the sole exception of lithium, which must be carried across the blood–brain barrier by other means.Review Questions•How do neurons differ from other cells in the body?•Draw a simplistic picture of a neuron and label the soma, nucleus, axon, terminal button, synaptic vesicles, dendrites, and receptors. Explain why it is “simplistic.”•What is the function of the blood-brain barrier and why is it important to designers of psychotropic medications?•How has our understanding of glial cells progressed in the 21st century?SECTION FOUR: TYPES OF NEUROTRANSMITTERSLearning Objectives•Generally understand what makes a ligand a neurotransmitter.•Be able to identify both excitatory and inhibitory neurotransmitters.•Be able to describe the difference between polypharmacy and co-treatment.The brain has literally dozens of known or suspected neurotransmitters. Scientists may discover many more. To be considered a neurotransmitter, a substance must (1) be synthesized in thepresynapticneuron, (2) be released from the presynaptic terminal, (3) cause excitatory or inhibitory signals, and (4) have some mechanism for removing it from the site of action (Churchland, 1995). Despite the number of existing neurotransmitters, only a fraction of those we know of are affected directly by the psychotropic medications we discuss in this book.Table 2.1lists neurotransmitters commonly involved in the actions of psychotropic medications.Neurotransmitters are made fromprecursor compoundsin the neuron. You can think of precursors as the “raw materials” with which neurotransmitters are made. These compounds include amino acids, glucose, and certain amines such as choline. You take many of these precursors into your body through the foods you eat. Think of neurotransmitters as chemical messengers in the nervous system. As we explain later, when a cell fires and releases neurotransmitters, these same transmitters bind to receptors on other neurons, conveying information and further exciting or inhibiting neighboring neurons.TABLE 2.1Neurotransmitters Involved in Psychotropic Medications and Their Abbreviations Glutamate                                                                                          Glu Glu Gamma-aminobutyric acid                                                                GABA GABA Acetylcholine                                                                                     Ach Ach Dopamine                                                                                           DA DA Norepinephrine                                                                                   NE NE Epinephrine                                                                                        Epi Epi Serotonin                                                                                            5-HT 5-HT © Cengage Learning®Now we provide an overview of the primary neurotransmitters. Become generally acquainted with them, so that when we discuss mechanisms of action in drugs you can recognize the primary neurotransmitters involved. Although scientists generally think that typically neurons only produce one type of neurotransmitter, each neuron may be outfitted with receptors for multiple neurotransmitters. Thus, although typically a neuron that produces only dopamine releases only dopamine (there are always exceptions though), it can be affected by changes in available serotonin, norepinephrine, acetylcholine, and so on. This multiple sensitivity produces a “ripple effect”: Using a drug to affect the levels of only one neurotransmitter may end up affecting the levels of many neurotransmitters.GLUTAMATE (GLU)Glutamate (also calledglutamic acid) is one of the non-essential amino acids, meaning it is synthesized in the body and you do not have to acquire it in your diet. One of the main sources of glutamate in the body is the breakdown ofglucose. Most neurons have glutamate receptors. Glutamate generally serves an excitatory function, encouraging neurons to fire, and plays a key role in sensory functions and in some brain structures we have discussed in this chapter, including the pyramidal and extrapyramidal nervous systems, the hippocampus, and the cerebellum. Glutamate may be the dominant excitatory neurotransmitter in our brains. Julien et al. (2014) noted that a newer drug for narcolepsy actually works by augmenting glutamate neurotransmission (as opposed to drugs such as amphetamines that augment dopamine neurotransmission). Researchers hope that a drug augmenting glutamate transmission will not show the dependence-inducing properties that amphetamines have. In addition, drugs that modulate glutamate have been recently targeted as a possible intervention for Schizophrenia (Hasimoto, Malchow, Falkai, & Schmitt, 2013). This is difficult because too much glutamate can trigger seizures or kill brain cells while too little can cause comas (Locke, 2008).GAMMA-AMINOBUTYRIC ACID (GABA)Gamma-aminobutyric acid (GABA) is one of the amino acid neurotransmitters and occurs almost exclusively in the brain. GABA reduces the firing of neurons and may be the predominant inhibitory neurotransmitter of the brain. Paradoxically, glutamate is a precursor for GABA, but whereas glutamate is excitatory, GABA is inhibitory. GABA is so common in the central nervous system that neurologists believe a full one-third of synapses are receptive to it (Zillman, Spiers, & Culbertson, 2007). Although GABA is inhibitory, it is important not to oversimplify this into the erroneous belief that all GABA transmission “mellows you out.” For example, some areas of your brain (such as your sleep centers), when stimulated, calm you down. If GABA molecules inhibit these areas, then the end result is theoppositeof calming you down. GABA-ergic areas of the brain also help people control motor behavior. People withHuntington’s choreahave difficulty controlling their motor behaviors, and physiologists believe this is caused by losing GABA-ergic neurons (Zillman et al., 2007).ACETYLCHOLINE (ACH)Acetylcholine was the first major neurotransmitter to be identified in the 1920s. (Epinephrine was discovered in 1904 but is less important in psychopharmacology.) Acetylcholine is prominent in the peripheral and central nervous systems. It is present peripherally at the muscle–nerve connection for all voluntary muscles and at many involuntary nervous system synapses. The exact role of acetylcholine neurons is becoming clearer with research. Generally, they are believed to be involved in alertness, attention,and memory. Acetylcholine is made from choline (an amine and one of the B-complex vitamins) andacetate. Choline is supplied by foods such as kidneys, egg yolk, seeds, vegetables, and legumes. Acetylcholine has been linked to cognitive functioning, because Alzheimer’s-type dementia is correlated with the degeneration of acetylcholine-rich tissues in the brain. Many drugs that temporarily slow the progression of Alzheimer’s do so almost exclusively by enhancing the action of acetylcholine in the brain.MONOAMINE NEUROTRANSMITTERSMonoamine neurotransmitters are a class of neurotransmitters that share similarmolecular structures. The monoamines include dopamine, norepinephrine, epinephrine, and serotonin. A subclass of monoamines is the catecholamines. The three catecholamine neurotransmitters are dopamine, norepinephrine (in the central nervous system), and epinephrine in the peripheral nervous system. The first two play important roles in both legal and illegal psychotropic compounds.DOPAMINE (DA)Dopamine was discovered in 1958. Dopamine is a major transmitter in thecorpus striatum(cerebrum), regulating motor behavior and playing a large role in the so-called pleasure or reward centers. It is derived from tyrosine, which is an amino acid in our diets. The dopamine pathways in the frontal cortex,nucleus accumbens, andventral tegmental area(VTA) underlie the pleasure centers. The firing of dopamine neurons in these areas is augmented by certain drugs, which seems to lead some people to use these drugs in ways that are described as “abuse” and that may induce psychological or physical dependence. We look at primary dopamine tracts when we discuss antipsychotic drugs inChapter Seven.NOREPINEPHRINE (NE)In the 1930s, the neurotransmitter norepinephrine was found in both the central and peripheral nervous systems and in the sympathetic nerves of the autonomic nervous system (governing heart rate, blood pressure, bronchial dilation, and so forth). Norepinephrine is derived from tyrosine (an amino acid), and the cell bodies of most norepinephrine neurons are located in the brain stem in the locus coeruleus. From this area, norepinephrine neurons project widely throughout the brain and are involved in many responses, including feelings of reward, pain relief, mood, memory, and hormonal functioning.“It’s Greek to Me”A few notes on terms: The wordnorepinephrineis synonymous withnoradrenaline. Norepinephrine is similar to epinephrine, which is a hormone produced by the adrenal medulla (the core of the adrenal gland).Epinephrineis synonymous withadrenaline. You may ask (as we did), “Why are there two words for both norepinephrine and epinephrine?” Good question, and we don’t have an answer, but here is a little background.Basically, one word is derived from the Greek language and the other from Latin.Epinephrineis derived from Greek (epi, “on”;nephron, “kidney”).Adrenalis derived from Latin (ad, “toward”;renal, “kidney”). The prefix“nor”indicates that norepinephrine is a precursor to epinephrine. So to say a drug is “noradrenergic” means it enhances the action of noradrenaline/norepinephrine.SEROTONIN (5-HT)Serotonin is distributed throughout the body. Researchers in the 1950s initially investigated it as a central nervous system transmitter, because of its similarity in structure tolysergic acid diethylamide (LSD). In the central nervous system, serotonin is the primary transmitter of the raphe nuclei, the group of neurons in the medulla and pons. From there, these neurons project throughout the cerebral cortex, hippocampus, hypothalamus, and limbic system (Julien, 2001). Serotonin is heavily involved in the sleep–wake cycle as well as in sexuality, mood, and emotion. This is why side effects from serotonergic drugs often include sleep and sexual side effects. Serotonin is derived from tryptophan, an essentialamino acid that people must obtain through diet. Although depriving people of tryptophan is correlated with depressive symptoms in some but not all study participants, adding extra tryptophan does nothing to alleviate depressive symptoms (Hansen et al., 2011; Jacobson, Medvedev, & Caron, 2012; Parker & Brotchie, 2011).REALITY IS COMPLEX AND …It is important to understand that each neurotransmitter may have a number of different receptors to which it can bind. These subfamilies of receptors may play varying roles in mental/emotional disorders. For example, there are numerous serotonin (5-HT) receptors, variously referred to by numeric labels (5-HT1, 5-HT2, 5-HT3, and so on) (Bloom et al., 2005).Julien et al. (2014) have noted that researchers think neurotransmitters fit various receptors much like a key fits a particular lock. As Sopolsky (2005) noted, this is a time-worn and almost cliché way of teaching the relation between receptors and neurotransmitters but it has persisted because it communicates the basic idea. Thus, a drug that mimics the action of serotonin by binding to serotonin receptors may interact differently with different receptor subfamilies. This also has implications for the number of side effects a drug may have. Drugs described as “dirty” affect several receptors and subfamilies of receptors and have more side effects. The “cleaner” the drug is, the more focused its action and the fewer its side effects.Another complexity is important here. Although researchers once hoped that certain neurochemicals would be specific to certain brain sites, they aren’t. Moreover, there is no sharp distinction between chemicals found in the brain and hormones found in rest of the body. Hormones once thought unique to the rest of the body have been found in the brain, and chemicals once thought unique to the brain have been found in the rest of the body. In addition, neurotransmitters may work with other peptides (chain-links of amino acids), forming cotransmitter pairs. For example, dopamine works with enkephalin (a naturally occurring protein with morphine-like properties). Researchers are beginning to see that to influence neurotransmission, pharmacologists may need multiple drug actions. This area in the leading edge of psychopharmacology is also known aspolypharmacy, which is the use of multiple psychotropic medications to bring about symptom relief. This practice may result in a person being placed on numerous drugs because of the presumed interactions among the drugs. Thus, you may hear of a drug such as methylphenidate/Ritalin “potentiating” fluoxetine/Prozac. In that instance, the methylphenidate/Ritalin enhances the action of the fluoxetine/Prozac. Polypharmacy has also led to the practice of combining two medications in a formulation for a single dose. An example is one of the newest mood-stabilizing medications olanzapine and fluoxetine/Symbyax, which combines an antipsychotic medication (olanzapine) and an antidepressant (fluoxetine). When such a combination has been tested in double-blind, placebo controlled, multi-site studies and found statistically significant, we no longer call it polypharmacy but rather co-therapy. This change in label means it has been tested and works better than a single drug alone. One problem with polypharmacy is that it is too easy for a client to end up on more than one medication while no one really knows which med is doing what and whether they are all necessary (seehttp://www.tedxcle.com/dr-elliott-ingersoll/).Review Questions•What sorts of classifications make something a neurotransmitter?•Provide one example of an excitatory and inhibitory neurotransmitter.•What is the story between polypharmacy and co-therapy?SECTION FIVE: THE STORY OF NEUROTRANSMISSIONLearning Objectives•Understand the “wires and soup” metaphor.•Be able to outline the relationship between DNA, RNA, and mRNA.•Understand basic functions of transporters and enzymes.•Generally outline the story of neurotransmission including first and second messenger effects, neuronal firing, and the binding and reuptake/breakdown of neurotransmitters.Most psychopharmacology is the story of how different medications interfere with neurotransmission. If you become fluent in the language of neurotransmission, you can begin to understand the actions of medications on the brain. Stahl (2000) has offered two similes to help us understand neurotransmission: “wires” and “soup.” In some respects, the nervous system is like an electrical system (wires) in the sense that connections between neurons are like millions of phone wires within thousands of cables. The big difference is that, unlike a phone or electrical system, neurotransmission is not all electrical. The impulse from the receptor of a cell to the terminal button is electrical. After the cell fires, the neuron sends neurotransmitters out into the extracellular fluid (the chemical “soup”), where the chemical messengers (the neurotransmitters) bind to receptors on other neurons. So neurotransmission is both electrical and chemical. Psychotropic medications can exert effects on both dimensions of neurotransmission. Stahl also discusses the notion of time and neurotransmission. Some neurotransmitter signals are fast (such as GABA or glutamate signals that occur in milliseconds), whereas others are slower (such as norepinephrine, with a signal lasting up to several seconds).NEUROTRANSMISSION: THE TEAM PLAYERSWe now introduce some of the key players in neurotransmission. After this we present the entire process of neurotransmission, and then the ways psychotropic drugs interfere with the key players and the process to exert their influence on the nervous system.Deoxyribonucleic Acid (DNA)Deoxyribonucleic acid (DNA) is amacromolecule, a very large molecule consisting of hundreds or thousands of atoms, housed in the nucleus of the neuron that has two interconnected helical strands (the well-known double-helix shape). These strands and associated proteins make up the chromosomes that contain the organism’s genetic code. When DNA is active, it makes ribonucleic acid (RNA) and gives RNA the genetic code. The messenger RNA then leaves the cell nucleus and attaches to ribosomes (protein structures that serve as the site of protein production) to create more proteins that serve as the basis for building other structures in the cell. Basically, the DNA acts as a template for messenger RNA synthesis; mRNA is a template for protein synthesis. DNA and RNA govern the production of enzymes, receptors, transporters, and other chemical supplies in and around the neuron’s nucleus. DNA is still an uncharted frontier. Although the Human Genome Project has led to advances in understanding DNA, approximately 97% of DNA sequences are noncoding sequences and are still not understood (Flam, 1994; Suurkula, 1996).TransportersTransporters are just what the name sounds like— they move things around inside the neuron, outside the neuron, and in and out of the neuron. In terms of neurotransmitters, transporters create a type of recycling program: First the cell fires neurotransmitters into the synaptic cleft. Then the neurotransmitter binds to a receptor. When it eventually unbinds,it is then picked up by this transporter, taken back inside the cell, and stored for future use. Some transporters move enzymes around the neuron so they can carry out their functions.EnzymesEnzymes have multiple functions in the neuron, but typically they put together substances such as neurotransmitters in some areas, whereas they may dismantle neurotransmitters at other areas. Enzymes are also transported (by transporters) outside the cell where they break down neurotransmitters in the synaptic cleft. The enzymes and other elements are then transported down the axon. Enzymes also provide the energy for the transporters to “recycle” the neurotransmitter in the synaptic cleft. Two examples of psychotropic drugs that act by inhibiting enzymes are donzepil/Aricept and tranylcypromine/Parnate. The enzyme acetylcholinesterase (AChE) breaks down acetylcholine (Ach) and the enzyme monoamine oxidase (MAO) breaks down monoamine neurotransmitters. Donzepil/Aricept inhibits AChE causing more Ach in the synapses which can help mild to moderate symptoms of Alzheimer’s type dementia. Drugs like tranylcypromine/Parnate inhibit MAO allowing more norepinephrine (NE) to be available in the synapses which can help symptoms of depression.ReceptorsReceptors are large molecules that are proteins (chains of amino acids) created in the soma (cell body) and transported by transporter molecules to different parts of the neuron. There are hundreds of types of receptors with specified functions. Receptors are inserted through the neuronal membrane by enzymes to perform these functions in neurotransmission. Receptors weave in and out of the cell membrane (often in a circular fashion), so part of them is outside the cell (extracellular) and part of them is inside the cell (intracellular). The binding site for the neurotransmitter is typically extracellular (outside the cell). There are many receptor subtypes. For example there are about a dozen serotonin receptor subtypes.Many different proteins may serve as receptors, there are some primary types worth mentioning.Ion channel receptors(ionotropic receptors) function asion channels. As Advokat et al. (2014) note these form a sort of pore that enlarges when certain neurotransmitters (and drugs) attach to them. This allows flow of a certain ion that could be positively (e.g., sodium) or negatively (e.g., chloride) charged. As we noted, an influx of positively charged ions will be excitatory to the cell and an influx of negatively charged ions will inhibit the cell. G-Protein-Coupled Receptors (GPCRs) are also called metabotropic receptors. Activating these receptors releases an intracellular guanosine-nucleotide binding protein (called a “G” protein for short) that controls enzyme functions in thepostsynapticneuron. Basically GPCRs change extracellular stimuli like drugs or neurotransmitters into intracellular signals (Advokat et al., 2014) through direct and indirect effects that will be discussed in the different drug classes covered in this book. Finally, carrier proteins are receptors that transport ligands such as neurotransmitters across cell membranes.BACK TO NEUROTRANSMITTERSAs we have already noted, enzymes in the cell make neurotransmitter molecules. The enzymes then package the neurotransmitter into synaptic vesicles that are transported to the terminal button for storage. The synaptic vesicles protect the neurotransmitter from other enzymes that break down the neurotransmitter.IONSIons are atoms or groups of atoms electrically charged by loss or gain of electrons. Cations are positively charged. Examples of cations are sodium (Na from the Latinnatrium) and potassium (K, from the Latinkalium). Anions are negatively charged ions. Chloride (Cl) is an example of an anion. Ions flow in and out of neurons, increasing or decreasing the electrical charge. If the charge is positive enough, the neuron fires. If the charge is negative enough, the neuron resists firing.ION CHANNELSAs noted above, ion channels are types of receptors that form channels or pores across the neuron membrane. They can open to allow positively or negatively charged ions into the channels, increasing or decreasing the chance that the neuron will fire depending on what sort of ion was let in. These channels can also remain closed. A cell in itsresting statehas anions intracellularly (inside the cell) and cations extracellularly (outside the cell). In this state the cell ispolarized, with the positively charged ions on the outside and the negatively charged ions on the perimeter of the inside. If cellular events increase this state by resisting opening the ion channels or by letting in only negatively charged ions, the cell ishyperpolarized, decreasing the chance it will fire. If ion channels open the cell to positively charged ions, it then becomesdepolarized, increasing the likelihood of firing.A VIEW WITHIN THE CELLYou can think of the cell as a little “universe.” In this universe, the DNA and mRNA are initiating protein synthesis in the ribosomes and those proteins are then used to create everything from enzymes to transporter molecules. The transporter molecules are busy transporting elements up and down the neuron axon, to and from the cell body, and moving in and out of the cell with other elements. The enzymes at some points are busy creating neurotransmitters from precursors, at other points dismantling neurotransmitters that have been fired, and at still other points providing energy for various functions of the cell.Some readers may find a manufacturing metaphor useful. In the metaphor, the DNA and mRNA are the “brains” behind the outfit, providing parts lists and plans about how each element will function. The enzymes and transporters are like workers with different functions. One of the primary products is the neurotransmitter, and it is packaged in the synaptic vesicles (much like workers producing cell phones may package them in a plastic container for shipping). The transporters are like tractor-trailer rigs that take care of transportation and shipping needs for the business.THE PROCESS OF NEUROTRANSMISSIONNow we describe a general sequence of events in neurotransmission. Again, remember that if you generally understand this sequence you will be able to understand how particular drugs interfere with the sequence and exert some of their effects. In this process, we talk about presynaptic neurons and postsynaptic neurons. These are really relative terms. To understand this, draw an image of three neurons side by side, using the image inFigure 2.4as a guide. Make sure each neuron you draw has a cell body (soma), dendrites with receptors, and a terminal button. Label the three neurons “A,” “B,” and “C.”In doing this, you can see that the terminal button of neuron A is next to the dendrites for neuron B. The terminal button for neuron B is next to the dendrites of neuron C, and so on. Although this figure is oversimplified, it communicates the basic details. Remember that a synapse is the point where neurons communicate with each other and the synaptic cleft is merely the slight space between these two points. So with regard to the synaptic cleft between neuron A and B, A is the presynaptic neuron and neuron B is the postsynaptic neuron. With regard to the synaptic cleft between neuron B and C, neuron B is the presynaptic neuron and neuron C is the postsynaptic neuron. The labels merely reflect the position of each neuron with respect to a particular synaptic cleft. So in one sense, every neuron is a presynaptic neuron to some other neuron and a postsynaptic neuron with respect to still others. Similarly, when you are driving on a crowded freeway, you are in front of some driver and behind some other driver.FIRST-MESSENGER EFFECTSWith the notion of presynaptic and postsynaptic neurons in mind, let’s begin with the example. Note that when a cell “fires” (sends neurotransmitters out into the synaptic cleft), we call thisexocytosis(“exo,” outside; “cytosis,” cell—outside the cell). So, in our example, neuron A fires and sends its chemical messengers (the neurotransmitters) out into the synaptic cleft. There some of them bind to receptors on neuron B. This initial binding is called a “first-messenger effect.” The effect can be an excitatory effect (depolarizing the cell to increase the likelihood of firing) or an inhibitory effect (hyperpolarizing the cell to decrease likelihood of firing). The effect is not tied so much to the neurotransmitter that is binding but to what ion channels the receptors it is binding to control. In some presentations, the excitatory or inhibitory effect is labeled with reference to the synapse.Figure 2.5, from Kalat (2001), shows an example.Remember that the resting state of the cell is called thepolarized state. If the receptors open ion channels that allow only negatively charged ions to filter into the cell, then the cell becomes hyperpolarized or less likely to fire. In this scenario, the first messenger effect is inhibitory. If the receptors to which neurotransmitters are binding open ion channels that let positively charged ions into the cell, then the cell becomes depolarized or more likely to fire. In this scenario, the first-messenger effect is excitatory.Remember, although part of the receptor is outside of the cell, the receptor also goes through the cell membrane into the cell. The chemical neurotransmitter binding at an excitatory synapse can initiate an electrical impulse that is carried through the receptor into the neuron. That signal may be strong enough to pass the axon hillock and to open ion channels that allow positively charged ions to enter the cell. The positively charged ions further facilitate the electrical signal, letting it continue down the axon to the terminal button. When a charge of sufficient intensity reaches the terminal button, the cell “fires” and the synaptic vesicle merges with the terminal button wall, letting neurotransmitter molecules flow out of the neuron.FIGURE 2.5The Process of Neural CommunicationOnce outside the neuron, the neurotransmitters are in the chemical soup (extracellular fluid). There they gravitate toward receptors and, if they fit the receptors in question, bind to them. Once bound, they may exert an agonist or antagonist effect on other cells, and the process continues. Remember that there are billions of neurons, with trillions of synapses where each may communicate with the others.Once fired from the neuron, neurotransmitters cannot just stay in the synaptic cleft indefinitely. They also do not bind forever to receptors but bind and release or are displaced by other molecules (drug or natural) that then bind to the receptor. The neurotransmitters are then either “recycled” by transporter molecules that carry them back into the cell for future use (reuptake), or they are deactivated by enzymes in the extracellular fluid and their constituent parts are either destroyed or recycled as precursors. Precursors derived from used neurotransmitter or from dietary intake are carried into the cell and then used to create the various elements we have been discussing here.SECOND-MESSENGER EFFECTSIf the first messenger is the neurotransmitter, there are thensecond-messengersthat cause second-messenger effects. These take more time than first-messenger effects, are more complicated, but also have a profound impact on neurotransmission. For example if a neurotransmitter attaches to a receptor it changes the shape of the receptor. Next it activates a “G” protein (discussed above) inside the cell membrane. The released element can then directly activate things like ion channels or indirectly activate enzymes like adenylyl cyclase. In this case the adenylyl cyclase then activates cyclic adenosine monophosphate (cyclic AMP) which is called the second messenger. The second messenger can have farther reaching effects like opening ion channels, changing enzymatic activities, or even affecting gene expression (Advokat et al., 2014). Compared with first-messenger effects, these second-messenger effects take longer to occur and last longer after they occur. The benefit of second-messenger effects is that they provide the cell with an efficient way to extend and amplify the cell’s response to the transmitter (Bloom et al., 2005).These first- and second-messenger effects may seem hard to imagine at first, but bear in mind that we are really just reviewing a sequence of events that affect the way the cell functions. Understanding of these events is still in the embryonic stage and will likely change a great deal over the next few years. Just remember that it is important to generally understand the sequence of neuronal events so you can understand (1) how psychotropic medications interfere with those events and (2) what effects are then correlated with specific types of interference. It is interesting to note that researchers hypothesize that second-messenger events can reach all the way back to the cell nucleus, where they may decrease the creation of receptors, reducing the sensitivity of the neuron. This effect, calleddownregulation, is one of the effects in a chain of events correlated with antidepressant-induced improvement in symptoms of depression. We return to this effect inChapter Five. A second-messenger effect can also increase the synthesis of receptors, increasing the sensitivity of the neuron. This is calledupregulation. Obviously not all these effects are necessarily good or therapeutic effects. These unwanted effects are calledside effects, and one example caused by upregulation istardive dyskinesia, an involuntary movement disorder. This is a side effect of older antipsychotic medications to which we return inChapter Seven. We do want to note here that the further away from a first-messenger effect, the less well understood are the mechanisms of action.A QUICK REVIEWLet’s review this information: A neuron gets a chemical impulse from a neurotransmitter that (via a first- or second-messenger system) may open ion channels or keep them closed. Depending on which channels are open, this leads the neuron to fire or not fire (exocytosis).Firing causes the release of stored neurotransmitter and related events (exocytosis). The neurotransmitters shoot across the neuronal synapse to bind to receptors. Neurotransmitter binding to receptor is analogous to a key fitting into a lock. If the neurotransmitter in question (key) does not fit into the receptor structure (lock), binding does not occur there. If the fit is good enough, however, the chemical signal is changed into another electrical signal, and the process goes on.WHAT HAPPENS WHEN NEUROTRANSMITTERS BIND TO RECEPTORS?The neurotransmitter binding to the receptor is the first messenger. It may trigger changes alone or in the cell through second messengers. As a first messenger (quick signal), the neurotransmitter may alter the neuron’s ionic gradient to make it fire, releasing more neurotransmitter. Depending on what type of receptor the neurotransmitter is binding to, it may inhibit the cell, preventing exocytosis.The second messenger (slow signal) is an intracellular chain reaction created by the first-messenger neurotransmitter occupying the receptor. As noted, in second-messenger systems the neurotransmitter may change the shape of the intracellular part of the receptor. This change then triggers release of a portion of a G protein to either open ion channels or to bind intracellularly to an enzyme that may then cause subsequent changes inside the cell.WHAT HAPPENS TO THE RELEASED NEUROTRANSMITTER?The released neurotransmitter may be recycled and taken back into the cell by transporter molecules to be used later, it may be broken down by enzymes and its precursors reused by the cell at some point, or it may be broken down and metabolized.This sequence of events can be altered by introducing psychotropic medications into the body, but as Stahl (2000) reminds us, that does not mean researchers have even begun to understand these events or all the effects of psychotropic medications on these events (let alone why any of the latter would decrease the symptoms of mental or emotional disorders). As Stahl wrote, most of these events are still mysteries to neuroscientists. It is important to note there are nonchemical means of altering this sequence of events, such as aerobic exercise and meditation. We say more about such means later in the book.Review Questions•What is the wire-soup metaphor regarding brain functioning?•What generally is the relationship between DNA, RNA, and mRNA?•What are some basic functions of transporter molecules and enzymes in the brain?•Give a rough outline of the “story” of neurotransmission.SECTION SIX: PHARMACODYNAMICS OR HOW PSYCHOTROPIC MEDICATIONS AFFECT NEUROTRANSMISSIONLearning Objectives•Be able to discuss what “agonism” and “antagonism” mean with regard to a drugs effects on the brain.•Describe three broad mechanisms of how drugs interfere with the process of neurotransmission.As we noted, we want you to understand the events of neurotransmission so that you can better understand how drugs interfere with those events and how the interference correlates with effects on symptoms. You have perhaps noticed that we keep avoiding the phrase “how drugs decrease symptoms of mental and emotional disorders.” We are consciously avoiding it because, in most cases, scientists simply don’t knowhow drugs specifically decrease symptoms. We want you to keep that in mind. This is one of the most compelling reasons for teaching psychopharmacology from multiple perspectives.What scientists do know a good deal about is pharmacodynamics, defined as how drugs act (or try to act) in and on the body. Although this is a broad area, for our purposes we focus on 11 general mechanisms of drug action, with an example of each. Bear in mind that psychotropic drugs do not use all these mechanisms of action and may also exert more than one mechanism.AGONISM AND ANTAGONISMWhen discussing agonism and antagonism, we refer to the various mechanisms as causing agonist or antagonist effects. The easiest way to think of agonist or antagonist effects is in terms of what the cell would do naturally. Something that assists or facilitates a cell’s functions is an agonist. An agonist facilitates an action. Something that interferes with an action is an antagonist. Because most cells fire naturally, anything that decreases the probability of this happening can be said to be an antagonist. Anything that increases the probability of this happening is an agonist. As usual, reality is more complex than this. This literature specifies not just agonism and antagonism but partial agonism, inverse agonism, partial inverse agonism, partial antagonism, inverse antagonism, and partial inverse antagonism. Although these concepts are much more exact, for this book the two broad categories of agonism and antagonism are enough.MECHANISMS OF ACTION WITH EFFECTS ON PRODUCTIONDrugs can affect the intracellular production of various elements. Earlier we noted that transporters and other proteins carry into the neuron precursors from which things such as neurotransmitter are created. Drugs can interfere with this process by acting like precursors and thus increasing the amount of precursor material available. One such drug is levodopa/Sinemet. This drug basically functions as a precursor to dopamine, allowing more dopamine to be made than normal. This is particularly important in Parkinson’s disease, because the disease causes the degeneration of dopamine neurons and thus decreases available dopamine. The drug, at least for a while, corrects the shortage caused by degeneration of dopamine neurons. Levodopa/Sinemet is an example of a drug exerting an agonist action, because its end result is to help the cells do what they would naturally do.Drugs can also inactivate enzymes whose job it is to create neurotransmitters. In this case, such a drug artificially decreases the levels of neurotransmitter in a cell by inactivating the enzymes that put the neurotransmitters together in the first place. Such a drug has an antagonist action, because it is stopping a cell from doing what it would do naturally. An example of a drug that acts in this manner is parachlorophenylalanine/Fenclonine (PCPA). In addition to being a mouthful to say, this drug inactivates enzymes that create serotonin. Because the release of serotonin is necessary for inducing sleep, such a drug causes insomnia. Interestingly, it may also be one of the few aphrodisiacs in existence. Because serotonin is also related to subduing sexual response, animal studies have correlated hypersexuality with its artificial decrease from taking PCPA.In our story of neurotransmission, we discussed transporters in and outside the cell that have various functions. One such function is the storage of newly created neurotransmitter molecules in the synaptic vesicles that protect them. The vesicles protect them from other enzymes whose job it is to break down neurotransmitter molecules. Thus, a drug that inactivates the transporter that carried the neurotransmitter into the synaptic vesicle leaves the neurotransmitter vulnerable to enzymatic breakdown. Such a drug, by interfering with this crucial storage, ultimately acts as an antagonist. Drugs using this mechanism of action also inactivate the proteins that help with exocytosis. A good example of a drug using these mechanisms of action is reserpine/Serpasil. Reserpine/Serapsil is no longer in the market, because it had unacceptable side effects, but its main mechanism of action affected acetylcholine, dopamine, norepinephrine, and serotonin.It was used to investigate depression because it caused a depressogenic (depression-inducing) response in animals. In the 1950s, physicians also used reserpine as an antipsychotic.Another mechanism of action that affects neurotransmitter production has to do with a special type of receptor called anautoreceptor. Autoreceptors seem to monitor levels of neurotransmitter in the synaptic cleft. For example, if there is enough dopamine in the synaptic cleft to bind to an autoreceptor, the autoreceptor sends a signal back into the neuron that basically says, “Slow down the synthesis and release of neurotransmitter.” When an autoreceptor is open, production continues as normal. Thus, two mechanisms of action here may affect neuronal production of neurotransmitter. The first is a drug that blocks an autoreceptor antagonistically (sending no signal for the cell to slow down production of neurotransmitter). Such a blockage in fact results in more neurotransmitter being produced and released, because the mechanism to signal a decrease has been effectively disabled. Clonidine/Catapres works in this manner. The other mechanism is to introduce a drug that mimics the endogenous neurotransmitter and increases the signals going into the cell to slow down production and release of neurotransmitter.MECHANISMS OF ACTION WITH EFFECTS ON RELEASE OF NEUROTRANSMITTERAs noted, the key element in exocytosis is the release of neurotransmitter into the synaptic cleft. Drugs may have mechanisms of action that can inhibit or facilitate this element. For example, drugs can stimulate the release of neurotransmitter from the terminal button. Such drugs act as agonists. Now here, remember our mantra. Students often assume that an agonist ultimately stimulates the nervous system, but this is clearly not true. We noted that the neurotransmitter GABA has an overall inhibiting influence on the nervous system, so if a drug facilitates the release of GABA that drug is still an agonist, whereas the end result of the GABA release is ultimately inhibitory. Two substances that work by stimulating the release of neurotransmitter from the terminal button are black widow spider venom and sea anemone toxin. Both substances pierce the membranes of the neuron and synaptic vesicles, causing the neurotransmitter to leak out. In the case of the human central nervous system, after the human has been bitten by a black widow spider, the venom causes acetylcholine to leak out. Although most bites from a black widow spider are not usually lethal because the spider injects minute amounts of toxin when biting, the venom itself is 15 times as toxic as the venom from a prairie rattlesnake.A substance that prevents the release of neurotransmitter from the neuron is botulinum toxin. This toxin has been anxiously discussed in the early 21st century as concerns about chemical warfare grow worldwide. Researchers estimate that one teaspoonful of pure botulinum toxin could kill the entire world’s population (Carlson, 2001). This poison works by preventing the release of acetylcholine, which can paralyze muscles (including those used to breathe) and cause death. Oddly enough, diluted botulinum toxin is used dermatologically. Injected locally into wrinkled skin, it paralyzes the area, locally giving the skin a smoother appearance. The drug is available under the brand name Botox.Another way that a drug can affect the release of neurotransmitter from the neuron is by imitating a first messenger. Nicotine is an excellent example. There are two subtypes of acetylcholine receptors: nicotinic and muscarinic. Acetylcholine binds to both types. Nicotine is structurally similar enough to acetylcholine to bind to the nicotinic receptors. Once there, it causes a release of the neurotransmitters in the neurons it binds to. This release is associated with the reinforcing properties of the drug. The body responds to the presence of nicotine by increasing the number of nicotinic receptors, resulting in the person needing more nicotine to get the desired effect (tolerance to the drug). This is why nicotine is associated with withdrawal symptoms. Although the number of nicotinic receptors eventually returns to theprenicotine state, this can take time, up to several months.Drugs can also interfere with first-messenger effects by blocking receptors. In this instance, they block the receptor and exert no action; thus such drugs are antagonists. Older antipsychotics act in this fashion by blocking dopamine receptors and not allowing dopamine to bind. Curare also acts in this way by blocking acetylcholine receptors. As you may recall, acetylcholine is the neurotransmitter at most muscle–nerve junctions, so blocking the receptors in this area causes the paralysis for which curare is so well known.MECHANISMS OF ACTION TARGETING NEUROTRANSMITTER DEACTIVATIONThe two final mechanisms of action we outline are particularly known in antidepressants. They are both agonists in that they facilitate the action and duration of neurotransmitters in the synaptic cleft. The first is enzyme deactivation. As you may recall, once neurotransmitters are released into the synaptic cleft, enzymes that are also in the extracellular fluid can deactivate the neurotransmitters. By deactivating the enzymes that deactivate the neurotransmitters, a drug can artificially lengthen the amount of time the neurotransmitters can exert their influence in the synaptic cleft. Antidepressants calledmonoamine oxidase inhibitors(MAO inhibitors) work in this manner. The second mechanism of action that targets neurotransmitter deactivation is calledreuptake inhibition. You will also recall that when neurotransmitters are in the synaptic cleft, they can be picked up by proteins calledtransporter moleculesand taken back into the cell to be recycled. If a drug disables or slows down these transporter molecules, this drug effectively increases the length of time the neurotransmitters can exert their influence. Almost every antidepressant on the market uses this mechanism in some manner (except for MAO inhibitors).Remember that a drug can use more than one of these mechanisms of action. It is also important to remember scientists simply do not know all the mechanisms of action for many drugs. It is hoped that future research will help map these mechanisms more effectively.Review Questions•Define “agonism” and “antagonism” with regard to the effects of drugs on the brain.•Describe three broad mechanisms that drugs can use to interfere with neurotransmission.SUMMARYAlthough an integrative study of psychopharmacology involves more than physiology, physiology forms the base knowledge in the field. This knowledge base focuses on how psychotropic medications affect the central nervous system, which includes the brain and spinal cord. Medications can also impact the peripheral nervous system, including the sympathetic and parasympathetic nervous systems.Understanding the story of neurotransmission is also crucial to understanding how psychotropic medication works. This understanding begins with learning about the structure of neurons, neurotransmitters, and their functions and interactions. The story of neurotransmission includes how neurotransmitters bind to receptors on neurons and the effects of this binding. Psychotropic medications can mimic or block binding, producing effects on the central nervous system. Once you understand the story of neurotransmission, you will better understand how psychotropic medications interfere with neurotransmission to produce various effects (some desired, some not).This chapter has covered what we believe to be the most pertinent material on psychopharmacology from the medical model perspective. A basic understanding of the brain structures as well as the events involved in neurotransmission will facilitate mastering the subsequent material in the book on specific types of medications. We cannot overemphasize the importance of this, and we encourage the reader to work (in groups or individually) with the following Study Questions and Exercises.CASE OF COLLEENColleen is a 45-year-old single woman who has suffered from depression for 15 years. She has gotten relief from many SSRIs, but their effectiveness diminishes over time. She and her psychiatrist have tried fluoxetine, paroxetine, sertraline, and currently escitalopram oxalate. Colleen continues to complain of depressive mood, anhedonia at times, and a general lack of direction in her life. Her psychiatrist first considered a course of a low dose of valproate, a mood stabilizer, to ease her symptoms, but then remembered the six studies indicating that there is efficacy in combining aripiprazole, an atypical antipsychotic, in a very low dose with an SSRI.Colleen agreed to try aripiprazole at 2 mg to determine if it could assist her. After eight days on the aripiprazole, Colleen noticed that she was agitated all the time and even very angry. This was not like her and she called her psychiatrist and, after a short discussion, he told Colleen to stop taking the aripiprazole immediately. In less than 36 hours, Colleen felt less agitated and angry. She continues to work with her psychiatrist and therapist on her depression.Questions About the Case of Colleen1.This case serves to introduce you to some of the dilemmas of psychopharmacology. Carefully discuss each concern with your instructor as each will serve as an advance organizer for a unit of the course. Almost every sentence stimulates a potential dilemma.2.It appears that the use of aripiprazole triggered a negative pharmacodynamic reaction with Colleen. Speculate as to what you think might have happened?CLASS EXERCISE: THE PSYCHODRAMATIC NEURONUsing placards that students can hang around their necks, label the primary parts in the story of neurotransmission. You will need cards to assign the following parts:•Three receptors•Three synaptic vesicles•One transporter molecule•One electrical charge•Two enzymes•Two ion channelsMark off an area in your classroom to create a psychodramatic neuron. You can use a table or desk for the synaptic cleft. On one side, line up the synaptic vesicles (in the terminal button) of the presynaptic neuron. On the other side, line up the receptors. One enzyme stands at the end of the row opposite the makeshift cleft. This enzyme is going to put a neurotransmitter together from precursors. The other enzyme and one transporter molecule stand at the side of the table representing the cleft. These will compete for the neurotransmitter once it has bound to and released from the receptors. The person playing the electrical charge stands at the end of the row opposite the makeshift cleft. The people playing the ion channels stand outside the row; one holds a sign indicating a positive electrical charge whereas the other holds a sign indicating a negative electrical charge. Use Lego-type pieces for the neurotransmitter— about four pieces per neurotransmitter.The action starts with each synaptic vesicle holding three neurotransmitters (each made of at least four Lego pieces). The electrical charge moves down the axon (the row). If the negative ion channel sign is in the row, the charge must stop and return to the top of the row. If the positive ion channel sign is in the row, the charge can proceed to the end, tapping the synaptic vesicles, which is their cue to “fire” the neurotransmitter into the cleft (set the Lego pieces on the table). The receptors should then pick up the neurotransmitter, one per hand only, count to five, then set them back down on the table. At this point, the enzyme and transporter compete for the released neurotransmitter. The transporter hands the neurotransmitter intact back to the synaptic vesicle, or the enzyme takes the neurotransmitter apart and carries the parts back to the enzyme near the soma, who puts them back together and carries them down the axon to the synapticvesicles. The instructor should direct the action, stopping to interview the various parts, asking them what they are doing, what they will do next, and so on. As different drugs are introduced throughout the course, you can write them into the script of the psychodramatic neuron to show how they interfere with the action and exert their influences.Although this exercise may seem odd, it really helps conceptualize the story of neurotransmission. The first author went to a Halloween party (come as your favorite neuron part) where the game was played well into the night.CHAPTER THREEPharmacokinetics: How the Body Acts on Psychotropic MedicationsPharmacokinetics is what your body does with a drug once you ingest it. Pharmacokinetics are the processes by which drugs are absorbed by the body, distributed within the body, and then metabolized, and excreted (Carlson, 2012). Obviously, to be effective a drug must reach its intended site of action. For psychotropic drugs, this intended site is the central nervous system, so the primary barrier that a drug must somehow get across is the blood–brain barrier. Pharmacokinetics also involves understanding the time course of a drug’s effects (the intensity of the drug effect on the body across time). Understanding how a drug moves through the body and the length of time it takes to exert therapeutic effects can help clinicians understand what the client can and cannot expect from the drug. It is also important to understand that there is more than the drug involved in pharmacokinetics. For example, most of us know that grapefruit juice interferes with a large number of drugs making them less effective if they are taken around the same time as the grapefruit juice (Kiani & Imam, 2007; Marchetti & Schellens, 2007).This chapter is divided into five sections. Section One discusses how drugs are absorbed into the body and the various routes of administration. Section Two covers what happens when drug molecules get to the bloodstream. In Section Three, we discuss drug distribution and important concepts like half-life and maintenance dose. In Section Four, we introduce drug binding and the various types of drug tolerance that one may develop. Finally in Section Five, we give an overview of how drugs are eliminated from the body.SECTION ONE: DRUG ABSORPTIONLearning Objectives•Be able to describe the various routes of drug administration.•Understand why some methods of administration may be optimal for particular clients.•Understand the concept of Lipophilicity.How a drug gets into the bloodstream and is distributed throughout the body is referred to asdrug absorption. In psychopharmacology, the primary aim is for drugs to get across the blood–brain barrier and into the central nervous system, the brain specifically. How do we determine how fast a drug gets to the brain? How do we know how much of the drug ingested reaches the brain? The answers to these questions depend on multiple variables (Ettinger, 2011). Some of the answers are found by examining routes of administration.Routes of AdministrationWhat is the first thing you must do with a drug for it to have its desired effect? Take it, of course. There are several ways you can do this that we call routes of administration, although not all are commonly used for administering psychotropic medications. The most common route is oral. For a drug to be taken orally, the drug must be capable of being dissolved (soluble) and must retain its integrity in the stomach fluids. This is one reasonthere are no psychopharmacologically effective nicotine products one swallows. Nicotine cannot withstand stomach fluids and breaks down before it can get to the central nervous system to exert its effects. So if you hear of an energy drink advertising nicotine for the “extra jolt,” save your money. The closest to an oral administration one can get with nicotine is through gum, dissolving tabs or mouth spray (Bolliger, van Biljon, & Axelsson, 2007). The speed with which a substance moves from the site of administration to the bloodstream is called absorption and this rate varies depending on the route of administration. Following are summaries of the more common routes of administration some of which will not be as relevant to psychopharmacology but which we include here for the sake of thoroughness.1Oral AdministrationThe most common route of drug administration for psychotropic medications is oral administration. Drugs taken orally can be in the form of tablets, capsules, liquid, and other types of pills. Some of the delivery systems are designed to be time-released (such as capsules for time-released methylphenidate/Concerta/Focalin). These drugs have to dissolve in stomach fluid and pass through the walls of the digestive tract to reach capillaries. Then the molecules enter the bloodstream and will eventually cross the blood–brain barrier. Obviously the drug must also be able to withstand stomach acids and other substances that break down food. Many drugs are not fully absorbed until they reach the small intestine. How quickly the contents of the stomach move into the small intestine depends on whether food is fatty (fatty foods slow movement), the amount of food in the system, the amount of physical activity the person engages in all make it difficult to predict how long it will take for an orally administered drug to reach its intended site of action (Meyer & Quenzer, 2005). Advantages of oral administration include safety and ease-of-use. Disadvantages include being a slower route with different rates of absorption based on the body type, age, sex of the client and of course gastrointestinal side effects.The fat solubility of the drug molecule also plays a role.Lipophilicity(think: “liposuction”) refers to the fat solubility of a compound. Because the walls of the intestines, blood vessels, and neurons are composed of fats calledlipids. The more fat soluble a drug is, the more easily it crosses these barriers. Some drugs, such as lithium, are not at all fat soluble (lipophilicitous) and must attach to another molecule and be carried across the barriers.InhalationInhalation is a predictable and direct route of administration with many applications. Inhalation is a fast and efficient delivery system because the lungs (part of thepulmonary system) constitute a large surface for absorption that is rich with capillaries that send substances directly to the brain without going through the heart first (Meyer & Quenzer, 2005). Recreational drug users such as cigarette smokers learn early on how efficient and rewarding this delivery system can be. Although we know of no psychotropic compounds taken by inhaler (other than experimental nicotine mouth sprays), cannabis (which has psychotropic properties) inhalers have been examined by the United Kingdom and Canada for administration of medical marijuana through vaporization. Vaporizers like the “Volcano” seem to be able to deliver cannabis with fewer harmful toxins like carbon monoxide, benzene, and other known carcinogens (Frood, 2007a). At the time of this writing, the states of Washington and Colorado decriminalized marijuana although federal laws still prohibit its use. Time will tell if this drug will make its way into the licit psychotropic substances (Frood, 2007b).InjectionThere are several types of injection: Subcutaneous, intramuscular, intravenous, and epidural. Subcutaneous is an injection just below the skin. The absorption depends on the rate of blood flow to the area of injection but the absorption rate is usually slow and prolonged. Drugs that are injected subcutaneously include hormones, birth controldrugs, and drugs for migraine headaches like Sumatriptan/Imitrex. Intramuscular injections are slow acting but produce more even absorption. Depending on the injection site and the blood flow to that area absorption usually occurs within an hour. Drugs can be mixed with substances (e.g., oils) that can slow the absorption. Many antipsychotics are now administered intramuscularly because disorders such as Schizophrenia frequently disrupt cognitive functions and interfere with routines and remembering to take medications. Intravenous injections are directly into the bloodstream and are the most rapid and precise ways to administer a drug (Ettinger, 2011). In this method, the drug does not pass through the lungs or digestive system. The downside to intravenous administration is that complications can prove lethal because the drug is getting into the system so quickly and directly. Epidural injections are used primarily for spinal anesthetics. In these cases, the drugs are administered directly into the cerebrospinal fluid surrounding the spinal cord bypassing the blood–brain barrier. The most common use of these is for facilitating analgesia in childbirth but no psychotropic medications are administered in this manner.Transdermal AdministrationTransdermal administration is done through a “patch” technology where the drug to be administered is on a patch that is then attached via adhesive to the skin. Because the skin is resistant to water passing through but allows fat soluble molecules through this can be a useful formulation. Nicotine patches, opioids for pain, and contraceptives are all examples of drugs that may be administered this way. Recently, (Azzaro, Ziemniak, Kemper, Campbell, & VanDenBerg, 2007) the antidepressant selegiline (an MAO inhibitor) was approved in a transdermal formulation. Although transdermal administration is a way to get controlled rates of absorption, it can cause skin irritation in some clients.Rectal AdministrationRectal administration is less efficient than oral or inhaler administrations but can be useful for patients who have digestive tract difficulties. Again, we know of no rectally administered psychotropic medications. Although this route of administration would be faster acting than oral, the disadvantages are obvious to most people.Mucus Membrane(transmucosal)AdministrationDrugs can be administered via the mucus membranes (mouth or nose), which result in fairly direct absorption into the bloodstream. Drugs commonly administered this way include nicotine (gum), decongestants, and nitroglycerine for cardiac patients (Advocat, Comaty, & Julien 2014). This can be advantageous for clients like children who have trouble swallowing pills.Review Questions•Explain three routes of drug administration and some advantages and disadvantages of each.•What route of administration would be good for a client who suffers from cognitive symptoms and why?•Why is it important that psychotropic medications be highly fat soluble?SECTION TWO: GETTING TO THE BLOODSTREAMLearning Objectives•Understand what a protein transporter is and the role it could play in medications getting to their intended site of action.•Be able to describe the process of drug diffusion.•Be able to describe the blood-brain barrier, its function and how drugs pass through it.Cell Membrane PermeabilityOnce administered, a drug must pass through multiple membranes to reach the site of action which for psychotropic medications is the brain. The route of administration will determine which membranesthe drug must pass through. Regardless of the route of administration, the cells lining the stomach, lungs, and the cells making up skin, muscle, and fat cells are composed of aphospholipid biolayer(two layers of lipid molecules that form a polar membrane). Phospholipids are the major components of cell membranes (so named because they contain an organic molecule from the phosphate group). Remember that lipids are molecules including fats and it is fats that we are interested in here. As written above, the drug molecules must be fat-soluble enough to pass through these membranes. The head of a phospholipid is positively charged and the tail negatively charged (thus “polar” membrane). Although the head attracts water, the tails repel water and prevent water-soluble elements from getting through. Embedded in these phospholipid molecules are proteins that act as transporters. For something to pass through the cell membrane, they must be carried through by the transporter or be fat soluble, which, as stated, most psychotropic medications are (Ettinger, 2011).Drugs must also pass in and out of capillaries which are a route into the bloodstream. They are made of a single layer of cells that, though tightly packed, have gaps in them. Drug molecules can move through these gaps in a process calleddiffusion. This is how organisms exchange food, waste, gasses, and heat with their surroundings. The rate of diffusion is represented by Fick’s law, which states that diffusive flux goes from regions of high concentration to regions of low concentration. This is affected by the thickness of the membrane through which molecules are diffusing, the surface area for gas exchange, and the mass and fat solubility of the molecule. Movement across membranes is in the direction from higher to lower concentrations. The larger the concentration gradient (the difference between levels of the molecule between the two sides of the membrane) the more rapid the diffusion. Drugs that are lipid soluble move through cell membranes via passive diffusion, which leaves the water in the blood or stomach and moves into the membrane (Meyer & Quenzer, 2005).As noted inChapter Two, psychotropic medications must also cross the blood–brain barrier. The brain requires more protection from foreign substances than other organs so the capillary walls do not have gaps. The gaps are surrounded by a type of glial cell called anastrocyte. These make up the blood–brain barrier. Over 100 years ago, Paul Ehrlich discovered that if blue dye is injected into an animal’s bloodstream (in his case a rabbit’s bloodstream), all the tissues are tinted blueexceptthe brain. You must inject the dye into the brain ventricles to get that tissue to turn blue. Although Ehrlich was working for a dye company on a different project, he thus unwittingly discovered the blood–brain barrier. This barrier blocks many substances from entering the central nervous system. In some areas, the barrier is weaker than others, to allow specific functions that have developed through evolution. One example of such an area is thearea postrema, which signals vomiting. The barrier is weak here, so toxins in the blood can be detected. Once it detects toxins, the brain triggers the vomiting response to preserve the organism.The blood–brain barrier serves an important survival function by keeping foreign elements such as toxins out of the brain. But what about things such as nutrients? Nutrients such as glucose must be transported through the capillary walls by special proteins. This is very important, because to exert their effects all current psychotropic medications must reach the central nervous system. To do so, they must pass through the blood–brain barrier. The glial cells that make up the blood–brain barrier have a high fat content. The myelination of the brain in infancy is one reason babies need a lot of fat in their diet.Drugs will also cross the placental barrier. The placental barrier allows nutrients and oxygen from the mother’s blood to cross into the baby’s blood. Mothers taking medications are also passing some of those medications on to the baby. The evidence on psychotropic medications used during breastfeeding is at the time of this writing limited for most drugs but particularly antipsychotics, hypnotics, and anxiolytics. Because we cannot formulate any generalizations about the use of these medications due to the dearth of data there is inherent risk for breast-feeding mothers who choose to usepsychotropics. Fortinguerra, Clavenna, and Bonati (2014) analyzed 183 peer-reviewed papers that studied 62 psychotropic drugs. Of these only 30% were thought to be safe during lactation according to an evidence-based approach. Genung (2013) concluded that “medications have the same, though exaggerated, targets and side effects on infants as on adults. Therefore, each prescribed medication must be researched individually. Even small amounts of medications can accumulate to toxic amounts in breastfed infants” (p. 217).Review Questions•What is the role of transporters in drugs getting to the brain?•What is the process of drug diffusion?•Describe the blood–brain barrier, its function, what it is made of, and how it affects psychotropic medications.SECTION THREE: DRUG DISTRIBUTIONLearning Objectives•Be able to describe the concepts of half-life and steady state.•Understand what the cytochrome P450 enzyme system is and why it is important for drug metabolism.•Be able to describe what titration and a maintenance dose are.Once a drug is absorbed into the bloodstream it is distributed through the body in the circulating blood. In many cases most of the drug will not reach the intended site (in the case of psychotropic medications the receptors in the brain) but is active in other parts of the body. Advokat, Comaty, and Julien (2014) note that most of any dose of a psychoactive drug is circulating outside the brain and is not contributing directly to the pharmacological effects. This widespread distribution may contribute to side effects, for example, antidepressants causing nausea by their effects on the serotonin receptors in the digestive tract.Your entire blood volume circulates through your body approximately once per minute. Usually within this minute the drug taken is distributed throughout the bloodstream. The route of administration will affect how much of the drug actually makes it into the bloodstream. For example, after oral administration the drug is reduced by enzymes in the digestive tract. Then veins leading away from the digestive tract flow through the liver further metabolizing part of the drug. This is calledfirst-pass metabolismand may require that more of the drug be administered than if it were given intravenously (Advokat et al., 2014).A drug’s half-life tells us how long it stays in the body. The half-life is what the words sound like— the length of time it takes for the blood level of a drug to fall by half. So at one half-life, 50% of the initial dose is out of the bloodstream (much of it redistributed to the tissues of the body). At two half-lives, 75% of the initial dose is out of the bloodstream. At three half-lives, 87.5% of the drug is out of the bloodstream. So for each half-life, half of the drug remaining is redistributed out of the bloodstream. Advokat et al. (2014) estimate that the drug persists at low levels for at least six half-life cycles. Even though a drug half-life can be estimated it can vary person to person. Elderly people are going to take longer to metabolize a drug than a young person in their 20s. Half-life only applies to blood plasma levels, not the presence of the drug in other places like the central nervous system.Half-life is also used to gauge what is called the steady state of the drug in the patient’s body. This is roughly the amount of the drug in the patient’s blood with regular dosing. The goal is to match a particular level of the drug with therapeutic results and then match dosing to achieve that level. This latter then becomes the maintenance dose, the dose needed to maintain levels of the drug linked to therapeutic response. The process of arriving at an optimal maintenance dose is called titration. When a doctor increases or decreases the amount of the drug to maximize therapeutic response we say she is titrating the dose up or down.TABLE 3.1Five Important Pharmacokinetic Terms Half-life Amount of time required for plasma concentration of a drug to decrease by 50% after a person stops taking it. Steady state The state when the concentrations of a drug in a person’s bloodstream reach a plateau so that the amount being taken in each dose is roughly equivalent to the amount being eliminated. Loading dose An initial dose of drug that is higher than subsequent doses, given for the purpose of achieving therapeutic levels rapidly. Maintenance dose The regular dose of the medication that maintains the steady-state plasma concentration in the therapeutic range. Titration The art and science of balancing a drug dose against the patient’s symptoms. Upward titration is gradually increasing the dose, and downward titration is gradually decreasing the dose. © Cengage Learning®Whenever you put a drug into your system, your body begins metabolizing it and trying to get rid of it. Drugs leave the body through the urine, perspiration, and exhalation. The hepatic system (liver) is one of the main metabolizers of drugs. Enzymes break down the drugs and the most common enzyme family is theCytochrome P450 enzyme systemabout which more will be said later. The liver enzymes turn the drug into less active or inactive water soluble metabolites that are then sent to the renal system and filtered out by the kidneys. There are some terms related to drug metabolism that are helpful to know. The first iselimination half-life. The drug’s half-life is the amount of time it takes for half of the drug’s initial blood level to decrease by half or 50%. A drug’s half-life may range from hours to days. The prescribing doctor’s goal is to prescribe a dose of the drug that, based on the half-life, will result in a steady blood level of the drug sometimes calledsteady state.Table 3.1defines concepts related to pharmacokinetics: half-life, steady state, loading dose, maintenance dose, and titration. These terms are frequently used in medical practice and may be confusing to the layperson. Clients often ask questions about these terms. One client mistakenly thought he could stop taking medication after the loading dose because he interpreted “loading” in a manner akin to computer software—once loaded, no further loading needed. The half-life is particularly important in understanding how long it takes a drug to clear out of a person’s system. This concept is helpful in explaining to clients why they are still experiencing side effects days after discontinuing medication.Review Questions•What is the relationship between a drug half-life and a steady state of the same drug?•Describe the function of the cytochrome P450 enzyme system and its affects on psychotropic medications.•What is meant by a maintenance dose?SECTION FOUR: DRUG BINDING AND TYPES OF TOLERANCELearning Objectives•Be able to recite the primary flaws in the theory that mental disorders were caused by a chemical imbalance in the brain.•Understand depot binding and the effects on the plasma levels of medications.•Be able to describe the types of drug tolerance.Once in the blood plasma, drugs then are redistributed to various tissues including the central nervous system (a process labeled redistribution). The molecules then bind to particular target sites. In the case of psychopharmacology, these sites have typically been neurotransmitter receptor sites. As we will illustrate throughout this book, in the 20th century it was long believed (and the belief was perpetuated by billions of dollars in advertising and planned publications from pharmaceutical companies) that mental disorders were caused by a chemical imbalance in the brain.We now have enough evidence to know that, in fact, is not the case and the idea has been falsified. The fact that a chemical intervention alleviates or decreases symptoms in no way means the chemicals affected by the intervention were imbalanced to begin with anymore than if someone feels better after smoking marijuana it means they have a cannabinoid imbalance.In the past few years, pharmaceutical companies are closing their neuroscience research facilities (Greenberg, 2013). In part this has been becausedespitethe belief that psychotropic medications corrected a chemical imbalance, the success rate of many of these drugs is modest at best. [For example, meta-analyses suggest antidepressants are only better than placebo 50% of the time (Khan, Leventahl, Khan, & Brown, 2002).] Another problem has been a steep increase in the number of lawsuits and amounts in settlements where companies were fined for questionable practices linked to psychotropic medications. In 2012 alone, companies paid over $5 billion in fines related to allegations of fraud including misleading claims about drug safety (Associated Press, 2009; Isaacs, 2013). That said, it remains to be seen how much new research will be done on pharmacological interventions because we know that mental and emotional disorders are more complex than brain chemistry. Certainly current medications that target receptors sites will be used for symptom control so understanding binding is still important. Until we can understand the etiology of mental disorders, symptom control may be the best we can do.Although we know fromChapter Twothat drugs bind to receptors to cause main effects, it is important to note that drugs may also bind at sites where there appear to be no measurable effects. These sites are called drug depots and they include plasma protein, fat and muscle. Depot binding does effect drug action in that it decreases the concentration of the drug at sites of action because only freely circulating drugs can pass across membranes. Also because these molecules will eventually unbind and re-enter bloodstream it can lead to higherthan-expected plasma levels and in some cases drug overdose (Meyer & Quenzer, 2005).Types of ToleranceIt is important to generally understand the types of tolerance clients can develop to drugs. Please note that in this book we avoid using the word “addiction.” The emotional hysteria around this word, and the lack of operational definitions, make it too inexact to be helpful. Physical dependence is linked with the termaddictionand implies that withdrawal signs are “bad” and only linked to drugs of abuse. This is far from the truth because severe withdrawal signs can follow cessation of such therapeutic drugs such as SSRI antidepressants.Instead, we discuss types of tolerance and dependence. Advokat et al. (2014) definetoleranceas the state of reduced responsiveness to the same dose of a drug. This can be produced by a variety of mechanisms, all of which result in the person needing increased doses of the drug to achieve the effects previously provided by lower doses.Dependenceis defined as a physical tolerance produced by repeated administration of a drug and a concomitant withdrawal syndrome when the drug is discontinued. Julien outlines three primary types of tolerance: metabolic, cellular, and behavioral conditioning processes.Metabolic toleranceis an increase in the enzymes that metabolize a drug, an increase caused by the presence of that or similarly acting drug. The most common enzyme system for metabolizing drugs is thecytochrome P450 enzymefamily. These enzymes, produced in the liver, have evolved over 3.5 billion years to accomplish the detoxification (metabolism) of ingested elements such as chemicals and food toxins. There are several families ofthese enzymes, some more specific to certain substances than others. Thus, metabolic tolerance begins when you take a drug that is broken down by any one of these families. If you take the drug consistently, your body responds by elevating the level of enzymes needed to break the substance down. The elevated enzyme level breaks down the drug more efficiently, leading to the need for a larger dosage; thus the cycle begins. The drug, the amount taken, and the individual body’s response to it, all determine the pattern of metabolic tolerance. This pattern does not inevitably spiral out of control to the point where the drug cannot be used. For example, many people take benzodiazepines such as Valium or Xanax on an “as needed” (p.r.n., from the Latinpro re nata, meaning “as needed”) basis. Such a person may only take 0.25 mg of Xanax once or twice a week. Such a low dose is unlikely to produce any problems with metabolic tolerance. This raises another important point, though, namely that similar drugs can producecross-tolerance. For example, if the same person who took one dose of alprazolam (brand name Xanax) once or twice a week was in the habit of drinking two to three alcoholic beverages each day, probably he or she would not get as much response from the Xanax as someone who only drank two to three alcoholic beverages per week. The person drinking alcohol daily has likely developed some metabolic tolerance to it, and the families of enzymes that break down alcohol are also involved in breaking down Xanax, thus diminishing the effect of the latter. For the record, anyone taking a benzodiazepine such as Xanax or Valium should not drink alcohol.Cellular tolerance, which is more related to pharmacodynamics, occurs when receptors in the brain adapt to the continued presence of a drug. Two common forms of cellular adaptation are downregulation and upregulation. In downregulation, neurons decrease the number and/or sensitivity of receptors because of the presence of a drug. In upregulation, neuronsincreasethe number of receptors. Another type of tolerance isassociative tolerance. This is where one would display tolerance to a drug in some but not all settings. What seems to be the case is that contextual cues associated with drug onset act as conditioned stimuli that can bring about tolerance (Ettinger, 2011). This is one reason that if someone addicted to drugs returns to the same context they may have a higher chance of relapse. Finally,behavioral toleranceis similar tostate-dependent learning. When animals are given intoxicating doses of alcohol before a learning task, they subsequently tend to perform that particular task better when under the influence of alcohol than when sober. This is behavioral tolerance.Review Questions•Why did people believe mental disorders were caused by chemical imbalances in the brain and what is the main weakness in that idea?•What is depot binding?•List and describe the different types of drug tolerance.SECTION FIVE: ELIMINATION OF DRUGSLearning Objectives•Understand the role and relationship between the kidneys and liver in drug metabolism.•Understand the promise and obstacles of pharmacogenetics.The phrase “termination of drug action” refers primarily to the routes through which a drug leaves the body. These include bile (the fluid produced by the liver), the kidneys, lungs, and the skin. The majority of drugs are excreted by the kidneys and thus have to be transformed into more water soluble compounds (remember that psychotropic drugs typically begin as fat-soluble agents). In most cases, these transformations make the drugs less active as well. In this section, we will discuss the role of the kidneys and liver in drug elimination as well as other factors that may affect elimination.The Renal SystemThe renal or urinary system consists of two kidneys, ureters (tubes that propel urine from the kidneys to the bladder), bladder, and urethra, which connects the bladder to the genitals for removal of urine. Like the brain kidneys are amazing organs. They constitute about 1% of our body weight and (similar to the brain) receive about 20% of the blood supplied by each heart beat. The kidneys excrete the majority of body metabolism products using functional units called nephrons, which number anywhere between 800,000 and 1.5 million. Nephrons consist of a “knot” of capillaries. Our blood enters these capillaries from the renal artery. Nephrons maintain concentrations of water in the blood; regulate blood volume, blood pressure, and the blood’s acidity (ph); and process secretion and reabsorption of things like ions, carbohydrates, and amino acids. The fluids filtered out of the capillaries are held in a chamber called “Bowman’s Capsule” from which they collect in ducts and are passed into the bladder. Drugs that are fat soluble (lipophilicitous) can easily cross the membranes of the renal system. Because most psychotropic drugs have to be fat soluble to cross the blood–brain barrier, they are readily reabsorbed from the renal system and back into the bloodstream making the kidneys only one system through which psychotropic medications exit the body.The Liver and Drug MetabolismBecause the kidneys do not totally break down psychotropic medications, another system is necessary to effect their elimination from the body. The liver provides many functions including protein synthesis, production of enzymes for digestion and detoxification. The main tissue of the liver is made of hepatocytes and it is these that pick up reabsorbed psychotropic medications and transform them with enzymes that make them less fat soluble and more likely to be excreted in the urine. There are several enzyme systems or families in the liver but the most referenced in regard to pharmacokinetics is the cytochrome P450 enzyme system. According to Advokat et al. (2014), the genes involved in the development of this system originated over 3 billion years ago for the purpose of metabolizing and detoxifying elements from the environment that find their way into our system. The P450 enzyme family is frequently mentioned in package inserts and other information about drugs citing the effects of the drug on the P450 system.Other Factors Affecting PharmacokineticsWe have learned a great deal in the late 20th and early 21st centuries about variables that can affect a drug’s effects on the body. There are genes that can affect pharmacokinetics and the study of such factors is coming to be called pharmacogenetics (Perlis, 2007). One example is a gene labeled ABCB1 that is responsible for a protein (P-Glycoprotein) that regulates absorption and elimination of many psychotropic (and other) drugs. Variations of this gene can act as predictors of treatment outcome as well as the effects of polypharmacy (Akamine, Yasui-Furukori, Ieiri, & Uno, 2012). Advokat et al. (2014) wrote that as genetic testing becomes more common and affordable, testing will be accessible to determine how a person metabolizes certain drugs anywhere on a continuum from slow to fast. It should be noted that substantial ethical and financial obstacles must be dealt with before this is going to be a widespread practice (Morley & Hall, 2004; Mutsatsa & Currid, 2013).Another field that has grown in the 21st century isethnopharmacotherapy(now more frequently referred to as ethnopsychopharmacology) that explores differences in the way different groups are affected by medications. Although we each share over 99% of our genes with all other humans, small differences linked to race and ethnicity may play roles in how particular people respond to a medication. For example, studies have supported the idea that pharmacokinetics may vary in people of Asian descent resulting in different dosing requirements and side-effect profiles (Wong, 2012). A similar area is the growing discipline of developmental pharmacology. One of the great gaps of knowledge in psychotropic medication use is the long-term effects of medications in pediatric populations. The Clinton administration passed one of the first bills to offer incentives to companies for running more trials with children and adolescents but our knowledge is still far from complete. Currently, we know that there are significantdevelopmental differences in changes in drug absorption, distribution, metabolism, and elimination. There are also developmental differences in the development of enzymes to break down drugs (van den Anker, 2010). At the other end of the developmental spectrum we need more data on how psychotropic medications affect elderly clients. The same issues that are relevant in pediatric populations arise at the other end of the lifespan spectrum. Concerns about impaired absorption, factors slowing distribution and variables interfering with metabolism are all important aspects of what is coming to be called geriatric psychopharmacology (Grossberg, 2010; Howland, 2009b).