Chapter 6: The Age of Anxiety PDF

C H A P T E R S I X The Age of Anxiety The multiple perspectives we have been using Although psychotropic medications are available in this book are particularly useful in unde...

C H A P T E R S I X The Age of Anxiety The multiple perspectives we have been using Although psychotropic medications are available in this book are particularly useful in understand- for anxiety disorders, many psychological treatments ing the impact anxiety has on U.S. society. The also have excellent track records. Remember, from word “anxiety” comes from a Latin root meaning an integrative perspective it is not enough to describe to “choke or throttle” connoting a troubled state anxiety symptoms, posit a biological explanation, of mind (Tone, 2009). Anxiety disorders are then describe how certain drugs act biologically to believed to be the most common mental health (at least temporarily) decrease or eliminate these problem in the United States. Two common mea- symptoms. With sentient beings, we have to look sures are lifetime morbid risk (the theoretical risk to the psychological, cultural and social variables of getting a disorder at any point in life) and that contribute to anxiety. 12-month prevalence (the proportion of the pop- We recall a client (Elijah) who lived in what ulation thought to suffer from the disorder in any could be described as a “toxic environment.” 12-month period). Baxter et al. (2013) conducted Elijah’s urban residence was the regular scene of a meta-analysis of 87 studies from 44 countries violence, and he himself had witnessed two shoot- between 1980 and 2009. They found that anxiety ings in his 23 years. He was court-ordered to disorders are common across the globe with an esti- receive treatment for an alcohol-related charge mated current prevalence of approximately as much (drunk and disorderly conduct). Even after abstain- as 28% of the global population. The prevalence of ing from all drugs for 60 days, Elijah was what anxiety disorders in the United States is estimated could only be described as “a nervous wreck.” He for lifetime morbid risk/12-month prevalence as showed symptoms of both Panic Disorder and follows: Specific Phobia 18.4%/12.1%, Social Anxi- PTSD (the latter related to stimuli associated with ety Disorder 13%/7.4%, Post Traumatic Stress Dis- the shootings he had witnessed). In consultation order (PTSD) 10.1%/3.7%, Generalized Anxiety with a psychiatrist, who prescribed SSRI medication, Disorder 9%/2%, Separation Anxiety Disorder 8.7% Elijah asked why he had his symptoms, and the doc- /1.2%, and Panic Disorder, 6.8%/2.4%, (Kessler, tor replied, “Some people have a genetic predisposi- Petukhova, Sampson, Zaslovsky, & Wittchen, tion to such things.” As Charlie Brown would say, 2012). Although anxiety disorders are prominent, “Good grief!” In this client’s case, genetic predisposi- it is important to realize that their incidence has tion not withstanding, there were clearly psychologi- remained steady over several decades despite phar- cal, cultural, and social contributors to his anxiety. maceutically funded efforts to make the public think His alcohol use was a classic example of self- there is an epidemic that needs medicated (Baxter medication. Although the SSRI medication provided et al., 2014). a window of opportunity for Elijah, it was going to 120 Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 121 take far more to alleviate his anxiety. Tragically, Eli- SECTION ONE: OVERVIEW OF jah was stabbed in a fight at his residence, and ANXIOLYTIC MEDICATION AND although he recovered from that, he never re- entered treatment. As we have urged in previous THE CONSTRUCT OF ANXIETY chapters, mental health professionals must not lose sight of clients like Elijah nor surrender them to the partial truths of medical model explanations. Learning Objectives Although society has effective psychological Understand that there is a wide variety of anxiolytic interventions for anxiety, researchers estimate drugs. that only 30% of people suffering from an anxiety Have a working definition of anxiety. disorder seek treatment, although treatment is effective for 70 to 90% of those clients who seek it (Preston, O’Neal, & Talaga, 2002). Why is there Thirty years ago, we would probably have titled so much anxiety in this population? It is not this entire chapter “Central Nervous System enough for mental health professionals to treat cli- (CNS) Depressants,” because those were the pri- ents and refer them for psychiatric consultations. mary compounds available for treating anxiety. From an integrative perspective, we must wrestle Currently, psychotropic medications from numer- with the question of why there are so many anx- ous classes are used to treat anxiety symptoms, ious people. Although moderate alcohol use can including CNS depressants, SSRI antidepressants, be perfectly appropriate, mental health profes- and unique compounds such as buspirone (BuSpar). sionals need to ask why there is so much abuse There is currently research being done on develop- of alcohol in Western societies. When reflecting ing different benzodiazepines (Trincavelli, Da on cases like Elijah’s, therapists must also remem- Pozzo, Daniele, & Martini, 2012), anxiolytics ber that anxiety symptoms are just as prominent in from antibiotics (Johnstone et al., 2004) and from people living in nontoxic environments. What are neurosteroids (Nothdurfter et al., 2011). In addi- people so anxious about, and is medication really tion, more studies are examining melotonin the best solution? Although mental health clini- (Ochoa-Sanchez et al., 2012) and kava (Alramad- cians must know about medications that can pro- han et al., 2012), which we discuss further in the vide relief for clients, they must also address these chapter on herbaceuticals. In general, anxiolytics are broader questions. the most commonly used psychotropic medications This chapter is divided into eight sections. Sec- and general practitioners (nonpsychiatrists) prescribe tion One provides an overview of anxiolytic med- the vast majority (less than 20% are prescribed by ications and the construct of anxiety. Section Two psychiatrists). This situation required us to structure focuses on areas of the central nervous system per- this chapter differently from the others in this book. tinent to anxiety and its treatment. Section Three For this chapter, we begin with a general discussion covers central nervous system depressants including of anxiety, then describe anxiety from the medical barbiturates and benzodiazepines. Section Four model perspective, and then describe the different covers nonbenzodiazepine alternatives in treating classes of drugs for anxiety. In discussing each class anxiety. Section Five introduces newer approaches of drugs, we outline some of the drug’s history; to treating anxiety. Section Six covers antidepres- mechanisms of action; side effects; and potential sants used as anxiolytics. Section Seven summarizes for tolerance, dependence, and overdose. Finally, anxiolytic therapy by diagnosis and Section Eight we outline recommended pharmacologic returns to important psychological, cultural, and approaches as well as other treatments for particular social considerations. anxiety disorders from DSM-5. The treatment of Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 122 PART TWO Introduction anxiety in children and adolescents will be covered As you can see from this summary, although his in a later chapter. explanations were mostly wrong, Freud was correct in differentiating panic from anxiety and would not The Construct of Anxiety be the last to do so. Anxiety is often differentiated Anxiety, in and of itself, is natural and adaptive. from panic and fear. Anxiety is defined as a future- A moderate amount of anxiety enhances physical oriented, negative mood state characterized by and intellectual performance. This is reflected in bodily symptoms of physical tension and by appre- what is called the Yerkes-Dodson law (Yerkes & hension about the future. A key feature of the appre- Dodson, 1908). Simply stated, it means people hension is related to the sense that the person cannot perform a little better when they are slightly anx- control upcoming events (Barlow & Durand, 2002). ious, but too much anxiety tends to impair perfor- Anxiety itself can be seen in the 11 Anxiety Disor- mance and too little leaves them unmotivated to do ders listed in the DSM-5, in several of the Personality their best (Barlow & Durand, 2002). You may have Disorders (Histrionic, Dependent, and Obsessive- been initially anxious picking up this book. If you Compulsive), Delirium, Delusional Disorder, Major were moderately anxious, the anxiety likely helped Depressive Disorder, and Schizophrenia. Anxiety you motivate yourself to get to this chapter. Readers Disorders are commonly comorbid with Substance who felt crippled with anxiety reading Chapter One Use Disorders (Wolitsky-Taylor, Operskalski, Ries, probably didn’t get this far. Craske, & Roy-Byrne, 2011). Fear is an immediate Anxiety was instrumental in the birth of psycho- alarm reaction to danger and is characterized by analysis and psychodynamic models of the mind. In autonomic nervous system stimulation (e.g., Inhibitions, Symptoms, and Anxiety (Freud, 1925), increased heart rate and respiration). The autonomic Freud unfolded his thinking about anxiety and its nervous system stimulation is thought to help the relationship to the structural model of the mind: id, person escape the feared stimulus. Panic, in contrast, ego, and superego. In this seminal work, he devel- is an abrupt onset of intense fear, usually accompa- oped the notion of anxiety neurosis and identified nied by physical symptoms such as heart palpitations, two forms. The first was a sense of worry or dread shortness of breath, and dizziness. Barlow and Dur- that originated in a repressed wish or thought that and (2002) described panic as a fear response when generated conscious and unconscious conflict and there is nothing (apparently) to be afraid of (in other was curable through the psychological treatment words, a false alarm). he developed into psychoanalysis. The second was an overwhelming sense of panic, accompanied by The Case of Marcia autonomic nervous system arousal (sweating, Marcia, a 36-year-old female teacher, married with increased heart rate, and diarrhea). This, he two adolescent teenagers, has struggled with mental thought, resulted from a buildup of libido and and emotional issues for the past 11 years. She has required a sexual outlet. Freud viewed anxiety as been diagnosed with (not at the same time) Major a result of conflict between unconscious sexual or Depressive Disorder, Dysthymic Disorder, Seasonal aggressive wishes in the id and the corresponding Affective Disorder, Avoidant Personality Disorder, punishment (or threat of punishment) from the and Personality Disorder Not Otherwise Specified superego. Anxiety is thus seen as a signal of danger (NOS). During the course of her treatment, Marcia in the unconscious, which could then result in a was a very compliant patient. She always took her dangerous behavior or in inhibition. In response medications, mostly TCAs, and seldom missed ther- to the signal, the ego mobilizes defense mechanisms apy sessions. During the 11 years of her treatment, to prevent unacceptable feelings from emerging she had cognitive-behavioral therapy with a feminist into consciousness. If the signal fails, the anxiety female therapist, gestalt therapy with a male thera- just keeps getting more intense and becomes pist, and holistic therapy with another female, and immobilizing. she tried various workshops and techniques such as Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 123 art therapy. Almost always, the intervention or that many anxiety symptoms often get subsumed theoretical approach was combined with a psycho- in a diagnosis of depression (as mentioned in Chap- tropic medication. Marcia improved slightly, only ter Three). It is true that Marcia did get depressed to return to what appeared to be a depressed and and exhibited depressive symptoms, but her pri- irritable state. mary problem was anxiety, showing the importance In the 10th year, after much frustration, Marcia of thorough diagnosis before any referral for was referred to a psychoanalytically oriented psy- medication. chotherapist who spent several sessions with her conducting an assessment. After this thorough and THEORIES OF ANXIOLYTIC ACTION extensive evaluation period, he made the diagnosis of Generalized Anxiety Disorder (GAD) and began As with depression, theories of anxiety rooted in to speak with her about the ways anxiety and panic the medical model hypothesize that some physio- manifested in her life. She seemed to talk about logical process is deficient or impaired and that this being incurably worried, exhausted, and never deficiency or impairment results in a person having able to relax. Marcia existed in a state of agitation. anxiety. Although some research supports this They also discovered together that the closer hypothesis, it is far from conclusive. As noted at Marcia got to a performance, a test in graduate the beginning of this chapter, there are more suc- school, giving a party, or being at a party, the cessful psychosocial interventions for anxiety than more she panicked and fretted. The therapist referred any other category of disorders. If anxiety were her to a psychiatrist for assessment for medications due solely to a physiological problem, why would and she prescribed clorazepate/Tranxene for her psychological interventions be so successful? Even anxious conditions. The combination of insight ther- the most rigorous medical model theory of anxiety apy and clorazepate/Tranxene was very beneficial. cannot dismiss the importance of the mind and of Marcia gradually decreased her irritability, learned the type of knowledge available from a psychologi- more about the triggers and pressures on her life cal perspective. from inside herself, and appeared less depressed. In the first session, Marcia said three things that Review Questions helped the therapist clarify his diagnosis: (1) “As I get closer to an obligation or performance, I begin What are some general types of anxiolytic to worry, ruminate, fret, and feel totally over- drugs? whelmed”; (2) “I fight these terrible battles within What is your working definition of anxiety? myself, should I do this or should I do that? How can I ever find a peace of mind?”; and (3) “Most of the time I disagree with my other doctors and therapists that I have depression, it always felt like SECTION TWO: THE CENTRAL something else, not depression.” Thus, from her NERVOUS SYSTEM: ANXIETY, BRAIN own words and her various therapeutic journeys, CIRCUITS, BRAIN STRUCTURES, AND it is evident that Marcia had a strong personal hunch that her previous diagnoses and treatments NEUROTRANSMITTERS were not quite accurate. (We might say her intra- psychic intuition was working fine.) Marcia was Learning Objectives most helped by a dynamic psychotherapy and a Understand the role of the Behavioral Inhibition benzodiazepine, clorazepate/Tranxene. Although System in Anxiety. we have not delved into the social and cultural Be able to articulate what neurotransmitter systems influences in Marcia’s case, it illustrates a very com- seem to be important in treating anxiety. mon error in current diagnostic thinking, namely Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 124 PART TWO Introduction In earlier chapters, we have described several brain negative ions (particularly chloride) to flow into the structures and some of the neurotransmitters in the neuron to decrease its excitability. Researchers brain associated with the types of symptoms psycho- hypothesize that an as-yet-undiscovered endogenous tropic medications are designed to treat. In this section, benzodiazepine molecule binds with receptors to we return to this topic to summarize the more popular allow this influx of chloride ions. The hypothesis medical model explanations of anxiety. A primary basically states that a deficiency of this yet-to-be- brain circuit associated with anxiety is called the behav- discovered substance causes anxiety disorders. Like ioral inhibition system (BIS) (Baskin-Somers, Wallace, the amine theory of antidepressant action, this hypoth- MacCoon, Curtin, & Newman, 2010; Gray, 1987; esis is a convenient extrapolation from the minimal McNaughton & Gray, 2000). This circuit leads from data available on these brain circuits but is hardly con- the limbic system to the frontal cortex and is triggered vincing when you consider all the environmental and from the brain stem. In the limbic system, meaning psychological factors that can trigger anxiety. Much attaches to incoming stimuli and the frontal cortex research on anxiety and brain structures points to processes executive functions. The circuit is triggered action in the amygdalae. The amygdalae are almond- by things such as unexpected events that act as signals shaped structures (one on each side of the brain) in the for danger; for example, abrupt changes in bodily limbic system that are involved in how we attach functioning or visual stimuli. In abrupt changes in emotional meaning to incoming stimuli. Advokat, body functioning, the signals arise from the brain Comaty, and Julien (2014) have summarized research stem, and in changes in visual stimuli they descend showing that electrical lesions of the amygdala result in from the cortex. Either way, BIS activation leads the an anxiolytic effect as well as research documenting person to freeze, experience anxiety, and evaluate the amygdala abnormalities in patients with Panic Disor- situation for danger (Keough & O’Conner, 2014). der. The latter two examples have a “chicken- This brain circuit is hypothesized to underlie the and-egg” problem. Miller, Piasecki, Peabody, and type of anxiety seen in GAD (Maack, Tull, & Gratz, Lonstein (2010) found that antagonism of GABAa in 2012) and creates effects that differ from the “fight anxiety-resistant rats increased anxiety. GABA is a or flight” circuit. The fight-or-flight circuit origi- neurotransmitter that tends to function in the brain nates in the brain stem (associated with vital body to calm the organism. As noted, although this research processes such as heart rate and respiration) and certainly supports the hypothesis that the amygdala proceeds through several limbic system structures. plays a role in anxiety symptoms, it does not confirm Stimulating this circuit produces an “alarm and escape that defects in the amygdala cause anxiety symptoms. response” that researchers believe manifests as panic such as that seen in Panic Disorder. In the panic Neurotransmitters Involved in Anxiety response, the limbic system, hypothalamus, and pitui- GABA has clearly been indicated as playing a role in tary gland release a cascade of neurotransmitters and relief from anxiety in that facilitation of GABA bind- hormones that prepare the body for action. Markar- ing is one mechanism that decreases anxiety. For ian, Pickett, Deveson, and Kanona (2013) have example, benzodiazepines facilitate the binding of also noted that the BIS can trigger anxiety when GABA to GABA receptors but do not directly stim- “… decreased responsiveness to rewards and a height- ulate GABA. By binding to an adjacent receptor, ened sensitivity to aversive stimuli may predispose for they change the shape of the GABA receptor making difficulties regulating emotions” (p. 285) suggesting a it more receptive to GABA molecules. Less well role for the BIS in personality disorders. understood are the roles of serotonin and norepi- nephrine. Currently, some medications prescribed A Hypothesized Braking System for anxiety target either serotonin (e.g., SSRI antide- Preston et al. (2002) note that the brain does have a pressants) and/or norepinephrine. Perhaps it is easier “brake system” of sorts. This brake system consists of to understand how norepinephrine is involved in the ion channels on most neurotransmitters that allow anxiety, because the fight-or-flight circuit includes Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 125 large releases of norepinephrine via the locus coeru- SECTION THREE: CENTRAL NERVOUS leus. The locus coeruleus (“blue disk”) is a small brain SYSTEM DEPRESSANTS structure (estimated to be about 10,000 neurons) whose neurons project to most other norepinephrine neurons in the brain. This structure can trigger the Learning Objectives release of norepinephrine, stimulating the sympa- Be able to state the differences between an anxiolytic thetic nervous system, resulting in tachycardia, and a hypnotic. tremor, sweating, and anxiety. One medication (clo- Know what the mechanisms of action are for barbi- nidine/Catapres) paradoxically treats such stimulation turates and benzodiazepines. by releasing norepinephrine as an alpha adrenergic Be able to list the advantages of benzodiazepines over receptor agonist, and this fools the brain into thinking barbiturates including the risks of overdose and the NE levels are higher than they really are and thus addiction. overall lowering NE levels. Although this medication Understand how the early anxiolytics like meprobe- successfully reduces physiological symptoms associ- mate became the first celebrity psychotropics. ated with noradrenergic overactivity, it does not relieve the psychological aspects of anxiety. Another neurotransmitter implicated in anxiety is Central nervous system depressants are a group of serotonin. Although its role is still unclear, apparently medications with diverse chemical structures that several serotonin agonists are helpful with anxiety. induce behavioral depression. They produce many One theory is that the brain structures implicated effects ranging from relief from anxiety and inhibi- in fear and anxiety (the hippocampus, amygdala, sep- tions, to inducing relaxation and sleep, to inducing tum, and dorsal raphe nucleus) are rich in 5-HT1a unconsciousness, general anesthesia, and (in over- receptors. In animal models, mice bred without these dose) coma and death. The predominant tendency receptors have heightened fear responses (Rambos of all these drugs is to inhibit the excitability of et al., 1998) so the fact that SSRI drugs activated neurons. them through reuptake inhibition is thought to Unfortunately, several terms are used to refer to account for their anxiolytic quality in some clients. CNS depressants, including sedatives, tranquilizers, In the last 20 years, researchers have made numer- hypnotics, and anxiolytics, which can cause confusion ous advances in conceptualizing and treating anxiety when you are first learning this material. In the first disorders. Some may argue that the anxiety disorders half of the 20th century, anxiety was not a common are so heterogeneous that it is not accurate to include construct and most patients were medicated with them all under one category, and there is much to “sedatives” for “anxiety neuroses.” These sedatives support this assertion. DSM-5 redesigned the anxiety were usually bromides or barbiturates combined disorder so that Obsessive Compulsive Disorder and with everything from cannabis to digitalis. With PTSD were moved out of Anxiety Disorders and refined diagnostic criteria, therapists would now into their own categories (Obsessive Compulsive say that many of these cases of “nerves” were actu- and related Disorders and Trauma and Stressor ally depression and would be more likely to treat Related Disorders respectively) (APA, 2013). them with compounds described in Chapter Five (Healy, 2002). The inducement of sleep is referred to as a “hyp- Review Questions notic effect.” This is inaccurate, because sleep What is the role of the Behavioral Inhibition induction is actually very different from what hap- System? pens (or doesn’t happen) in hypnosis, but the term was coined at a time when people believed hypno- What neurotransmitter systems seem impor- sis induced a sleeplike trance. Anxiolytics are drugs tant in the treatment of anxiety disorders? used for treating anxiety. We prefer the term Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 126 PART TWO Introduction anxiolytic throughout this book. The inaccurate also wonder what that is about. The answer is, as phrase “minor tranquilizers” is often used for anxio- mentioned earlier, that drug companies examine lytics but indicates only that these drugs treat milder the urine of subjects taking medications, to check symptoms than those treated by drugs labeled for active metabolites of the drug. These active “major tranquilizers.” As you will see in Chapter metabolites then provide the blueprint for synthesiz- Seven, the phrase “major tranquilizer” is also some- ing the compound or similar compounds. Barbitu- times misapplied to certain types of antipsychotic rates are derived from a parent compound barbituric medication. So many poorly chosen words! At acid that was first synthesized in 1864. It was mar- this point, the reader may conclude that the field keted in the United States as Veronal in 1903 and of psychopharmacology could benefit from the ser- because of loose guidelines governing pharmacy vices of a grammarian. Although we want readers to practice became a popular street drug known as be familiar with all these terms, we encourage the “goofballs” or “the poor man’s psychoanalysis” use of the more accurate terms “anxiolytics” and (Tone, 2009). There was also a combining of barbi- “hypnotics.” Anxiolytics are for decreasing anxiety turates with beer into a deadly concoction called a and hypnotics are for inducing sleep. Next we dis- “Wild Geronimo” (Rasmussen, 2009). cuss the CNS depressants that are currently (or his- Barbiturates have rapidly become the dinosaurs torically have been) used to treat anxiety. of drugs. As anxiolytics, they have been displaced by benzodiazepines. The effects of barbiturates are Barbiturates quite similar to those of alcohol, and their main The first barbiturates were created in the late 19th advantage is that they are cheap because their century and introduced to the United States in 1912, patents have expired (although this is not really an the first being phenobarbital. According to Julien advantage because most benzodiazepines are et al. (2011) between 1912 and 1950, hundreds of generic as well). Barbiturates differ from each barbiturates were tested and at least 50 were mar- other primarily in terms of how quickly they act keted. Although these medications are rarely used and in the intensity and duration of their action. for anxiety now, they dominated the antianxiety Half-lives range from three minutes to several market until about 1960, when their dangers and days. The differences in these properties are the drawbacks became widely known. We discuss barbi- main consideration in deciding which barbiturate turates in this book not so much because they are to use. The clinical use of these has declined often used but because their undesirable qualities set because they are lethal in overdose, the therapeutic the baseline for desirable qualities researchers wanted dose can be close to a toxic dose, they induce tol- in the anxiolytic drugs they were trying to develop erance and dependence, and they interact danger- and that currently dominate the market. As Stahl ously with other drugs (Advokat et al., 2014). (2000) points out, barbiturates do not really have a specific anxiolytic effect but merely reduce anxiety as Mechanisms of Action a side effect of their overall sedating effects, much Researchers once believed barbiturates caused a like drinking too much whisky might. general decrease in neuron excitability throughout The name “barbiturate” is said to have been cho- the nervous system. They believed the dominant sen either because the urine of a girl named Barbara action was to hyperpolarize many types of neurons was used to derive the compound or because it was (recall that “to hyperpolarize” means to increase the synthesized on St. Barbara’s Day (Snyder, 1996). For probability that a neuron will not fire). As with real- the curious minded, St. Barbara’s Day is December 4 ity, the truth appears more complex than that. In and she is the patroness of miners (and perhaps bar- Chapter Two, we wrote that glutamate tends to be biturate users, for all we know). She was martyred in a generally excitatory neurotransmitter and that C.E. 235 or 238. As far as using urine to synthesize GABA is generally an inhibitory neurotransmitter. compounds is concerned, the curious minded might Initial evidence in the late 20th century was that Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 127 barbiturates may act as glutamate antagonists (Zhu, nigra (motor skills), and the thalamus (processing Cottrell, & Kass, 1997), as well as GABA agonists sensory information). Barbiturate action on these (Tomlin, Jenkins, Lieb, & Franks, 1999). Although brain structures results in loss of coordination (ataxia), there are still aspects of barbiturate action we do not which increases with dosage. In terms of pharmaco- understand, the primary mechanisms seem to be kinetics, barbiturates are rapidly absorbed and distrib- these. First barbiturates act to prolong and potenti- uted to most body tissues. The ultra-short-acting ate the actions of GABA. At higher doses, they bind barbiturates are lipid soluble, cross the blood–brain to GABAa receptors acting directly on them. When barrier quickly, and can induce sleep in seconds. As a drug allows an influx of negatively charged ions noted, barbiturates differ in their length of action. into the neurons, it hyperpolarizes the neurons, Table 6.2 lists commonly used barbiturates, duration decreasing the probability that they will fire. Barbi- of effect, and common uses. turates also block AMPA/kainite receptors (gluta- mate receptors) decreasing the excitability of Common Side Effects neurons (Loscher & Rogawski, 2012). In addition Common side effects for barbiturates include behav- to facilitating the binding of GABA, barbiturates ioral depression, sleepiness and particularly disruption allow the influx of chloride, a negatively charged of REM sleep, motor and cognitive inhibition simi- ion, into the neurons. This effect accounts for the lar to those seen with alcohol, ataxia (loss of muscle increased toxicity of barbiturates compared to ben- coordination), and respiratory depression. Barbitu- zodiazepines (Advokat et al., 2014). Table 6.1 sum- rates are contraindicated in people with severe respi- marizes these hypothesized mechanisms of action in ratory disease or liver impairment, or who are barbiturates. You can imagine that combining all concomitantly using other CNS depressants. They these mechanisms of action would have a potent are clearly contraindicated for people who may be inhibiting effect on the nervous system. experiencing suicidal ideation, because the drugs are The neurons in the reticular activating system so easy to overdose on. (RAS) are particularly sensitive to barbiturate drugs. Tolerance and Dependence The RAS is involved in sleep, and this is one reason Barbiturates can induce both physical and psychological why barbiturates have a hypnotic effect. In addition, tolerance and dependence. Physical tolerance occurs sites of action include the cerebellar pyramidal via metabolic and cellular mechanisms. Metabolic tol- cells (involved in fine movement), the substantia erance is caused by an increase in the enzymes that metabolize barbiturates, resulting in a need for higher TABLE 6.1 Hypothesized Mechanisms of Action and higher doses. Cellular tolerance is the condition of in Barbiturate Medications Action Result TABLE 6.2 Examples of Barbiturate Drugs, Their First-messenger binding Facilitates the actions of to Duration of Effect, and Common Uses GABA receptors (acts as a GABA agonist) at those Duration Common receptor sites, decreasing Name of Effect Uses neuronal activity Thiopental 15 minutes Anesthetic Antagonism of glutamate Decreases neuronal Secobarbital 30 minutes Hypnotic activity Pentobarbital 4 hours Hypnotic Facilitation of chloride Further hyperpolarizes conductance into neurons neurons Phenobarbital 6 hours Anticonvulsant © Cengage Learning® © Cengage Learning® Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 128 PART TWO Introduction the neurons adapting to the presence of the drug. called his father, who even in his late 70s was Physical dependence is usually manifested by sleep dif- very sharp. His father remembered that he had ficulties when withdrawing from barbiturates, but taken pentobarbital/Nembutal and it was very withdrawal from high doses may also be accompanied helpful in low doses. He even remembered the by hallucinations and lethal convulsions (Advokat et al., physician who had prescribed the medication and 2014). The psychological dependence results from the encouraged Francis to give him a call, because he anxiolytic action. Depending on the individual and on was a friend and still in practice. Francis did, and the the set and setting of barbiturate administration, some doctor, simply basing his decision on how helpful people may experience a euphoric response that is also pentobarbital had been for his father, prescribed it linked to psychological dependence. The phrase “set for Francis. Francis did not seek assistance from and setting” refers to the mind-set of the person taking therapy or a psychiatrist. the drug and the physical place and context (setting) Francis began to use the sedative medication and where the person is taking a drug. found it very helpful. In fact, as time went on, he felt he needed more and more to get into the same Barbiturates and Overdose calm and soothing state. He slept longer and dee- Researchers estimate that barbiturates have been per, but found waking up very difficult. Even involved in nearly one third of drug-related deaths, though his physician warned him, Francis contin- including the deaths of several celebrities (Boston ued to need an ever greater supply of pentobarbital/ University Medical Center, 2002). Actresses Rachel Nembutal. Colleagues and friends began to worry Roberts and Carol Landis both committed suicide about Francis’s unpredictable behavior, his with barbiturates, and actresses Judy Garland and barbiturate-induced stupors, and his impaired Marilyn Monroe are said to have died of barbiturate decision-making skills. Francis continued to deteri- overdoses [although signs of overdose are still being orate until one day he didn’t come to work, nor did disputed in Monroe’s case (DiMaggio, 2006)]. he call. One of his worried colleagues went to his Although many of these deaths appear to be inten- home and found him in a deep sleep. He noticed tional suicides, others are accidental or possibly mur- the bottle of pentobarbital/Nembutal and immedi- ders. The effects of barbiturates can be so ately called for help from an emergency medical disorienting that a person may take one dose and technician (EMT). Francis was taken to a nearby then a second or third, having forgotten the pre- emergency clinic, revived and treated, and released vious doses. The toxicity of barbiturates is also with a referral to a psychiatrist who specialized in apparent in their approval as euthanasia agents for anxiety disorders. He never followed up. lab animals. Partly in response to the toxicity of We have not yet addressed a psychological factor barbiturates and to their multiple uses, pharmaceu- crucial to this case: Sometimes adult children who tical companies in the early to mid 20th century have overidentified with their parents seek out began to seek out nonbarbiturate alternatives with treatments that were helpful to their parents, even all the efficacy of barbiturates but without their if those treatments are outdated. Francis kept him- toxicity and dangers. self outside the appropriate treatment nucleus and found treatment for his anxiety in exactly the same The Case of Francis manner that his father had 20 years earlier—and it In the late 1990s, Francis, a 42-year-old unmarried was not effective. stock broker working in a high-powered invest- ment firm, found himself increasingly tense, edgy, Nonbarbiturate Alternatives: Mother’s and agitated, which he expressed in an aggressive Little Helpers temper with coworkers and friends. He remem- The subtitle of this section, “Mother’s Little Help- bered that his father in his 40s had taken some ers,” refers to the Rolling Stones song of the same sort of “-barbital” to help him calm down. He name that was Keith Richards and Mick Jagger’s Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 129 attempt to write a song that highlighted that drug magazine in February of 1957. According to problems are not confined to rock stars. The song is Andrea Tone’s research, in 1956 comedians made about a woman’s use of Valium to relieve the as many jokes about Miltown as they did about tedium of 1960s suburban life. Although Valium Elvis Presley (Tone, 2009, p. 65). Carter Wallace is a benzodiazepine, the benzodiazepine story pharmaceuticals also commissioned artist Salvadore begins with the search for nonbarbiturate alterna- Dali to create a walk-though art work (“Crisalida”) tives to anxiolysis. The aim of nonbarbiturate alter- that represented a person’s metamorphosis from the natives was to make a drug that was safer but still evils of nightmares to the divine dreams (all thanks reduced anxiety. Most of the nonbarbiturate alter- to meprobemate/Miltown of course). By the mid- natives were extremely similar to barbiturates in 1960s, more people than ever were taking prescrip- everything except molecular structure. Although tion anxiolytics. each one was initially marketed with great fanfare It should be noted that Frank Berger, who as a safe alternative to barbiturates, most were developed meprobamate/Miltown in 1950, was a equally dangerous and many were subsequently driving force against the popularization of medica- withdrawn from the market. The important result tions in the media as well as the use of drug com- of research on nonbarbiturate alternatives is that it pany representatives (called detail men in the 1950s) led to discovering the benzodiazepines, which we to educate physicians about medications. Because of discuss shortly. the money he brought to Wallace Laboratories, he had enormous influence. Insisting that good sales Meprobamate pitch would never be good science, he insisted In 1945, Czechoslovakian pharmacologist Frank that no detail men be used and that only ads that Berger was attempting to develop antibacterial are factual and educational should be released to agents. In his research he stumbled onto a sedating doctors. This rule held until Berger retired in compound that seemed to act like a barbiturate but 1973 (Tone, 2009). did not induce sleep as readily. He noted it seemed to induce “tranquilization” without necessarily The Quaalude Years inducing sleep, and that term was used in marketing Glutethimide/Doriden was introduced in 1954, the new compound, to present it as different from and methaqualone/Quaalude in 1965. Both were barbiturates. The compound was marketed as mep- hailed as nonbarbiturate alternatives but experi- robamate/Miltown in 1955 (Berger, 1970). Its pri- ence showed otherwise. In the 1970s and 1980s, mary success was that while reducing anxiety, it methaqualone/Quaalude rivaled marijuana and allowed people to remain awake. Like barbiturates, alcohol in level of abuse in the United States. By meprobemate/Miltown produced daytime seda- 1972, the practice of mixing methaqualone/Quaa- tion, relief from anxiety, and sometimes euphoria. lude with wine (“luding out”) was widespread Although not as toxic in overdose as barbiturates, across college campuses. Far from being nonbarbi- meprobemate/Miltown seemed to induce tolerance turate alternatives, glutethimide/Doriden and and dependence to the same degree and appeared methaqualone/Quaalude induced tolerance and more teratogenic than barbiturates. Meprobamate is dependence syndromes, and methaqualone/Quaa- still prescribed under the trade names Miltown as lude overdose proved even harder to treat than well as Equanil. barbiturate overdose. Methaqualone/Quaalude Meprobamate/Miltown also signaled the begin- was linked to numerous deaths, so it was banned ning of the celebrity endorsement for drugs. from the U.S. market in 1984. When taken off the Famous television star Milton Berle endorsed how market, methaphalone/Quaalude was placed on well meprobemate/Miltown made him feel and federal drug Schedule I, glutethimide/Doriden that he took it. His frequent testimonials earned was placed on Schedule II because of overdose him the nickname “Uncle Miltown” by Time deaths. Federal drug schedules are really a listing Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 130 PART TWO Introduction on five levels of drugs considered least to most Although scenarios such as John’s are not common dangerous. Schedule I is for drugs that are illicit today, clinicians recognize that in the history of devel- and supposedly have no medical uses although, as oping pharmaceuticals for mental and emotional dis- we will discuss later, this classification is debatable. orders some drugs, if abused, are very dangerous. As with barbiturates, euphoria associated with methaqualone/Quaalude seemed dependent on the set and setting of the drug user. In addition BENZODIAZEPINES to these drugs, carisaprodal/Soma was introduced Benzodiazepines are the prototypic anxiolytic and is technically a precursor to meprobemate/ medications. Over the past 40 years, barbiturates Miltown. This is still used as a muscle relaxant in were replaced by benzodiazepines, which are less the 21st century. A final note, chloral hydrate/ dependence inducing and have less abuse poten- Notec, which was synthesized in the 1800s, is tial. Benzodiazepines are still the leading treatment still abused as a CNS depressant which when com- for anxiety (Dell’osso & Lader, 2013) and cur- bined with alcohol is abused as a “date-rape” drug rently account for 90% of the anxiolytic market. (sometimes called a Mickey Finn) (Julien et al., In the United States, benzodiazepines are among 2011). These stories point out one pervasive prob- the most prescribed drugs (Baldwin, 2012). In a lem in psychopharmacology: once the “genii” is recent meta-analysis, Dell’osso and Lader (2013) out of the bottle (e.g., a drug is out on the market) found the most common psychiatric disorders it is almost impossible to put it back even though it benzodiazepines were prescribed for included may be criminalized. GAD, Obsessive Compulsive Disorder, Social Anxiety Disorder, PTSD, Panic Disorder, Agora- The Case of John phobia (Panic Disorder and Agoraphobia are John, a 36-year-old waiter, ex-con, and entrepre- stand-alone disorders in DSM-5 as well as ICD- neur, was a product of the late 1960s and early 10), Sleep Disorders, Depressive Disorders, Alco- 1970s. He believed one should be mellow at all hol Withdrawal (as a drug replacement strategy in times and should not become stressed under any Addiction Medicine), Delirium, Schizophrenia, circumstances. He was in a methadone treatment and for side effects from neuroleptic medications program to overcome his longstanding addiction (like haloperidol/Haldol or chlorpromazine/Tho- to heroin. With the pressures of new marriage and razine). As you can see, they are used across a a child, John felt he was becoming tense, agitated, broad spectrum of disorders. and anxious. He visited his primary care doctor and told him about everything except the metha- Some Anxiolytic History done treatment. After a brief assessment, the doc- Ever since Frank Berger had synthesized meprobam- tor prescribed methaqualone/Quaalude for John. ate, researchers had tried numerous combinations of The year was 1979, and given this drug’s street muscle relaxers and sedatives to come up with an reputation John was pleased. He called it his anxiolytic drug that would not totally sedate a person “cool-down script.” Soon it seemed to others but would decrease anxiety significantly. Following that the “ludes” became John’s substitute for his up on research begun by Berger, Leo Sternbach, a heroin addiction. He became a quasi-dealer for Polish chemist working for Roche Drug Company methaqualone/Quaalude and eventually became in New Jersey, first synthesized chlordiazepoxide/Lib- dependent on it. He deteriorated gradually but rium and diazepam/Valium. In trying to learn how eventually lost his job and family as a result of meprobemate/Miltown acted at a molecular level, this abuse/dependence. Fortunately, John had Sternbach and his colleague Earl Reeder were synthe- the inner resilience to request in-patient treat- sizing chemicals called quinazolines and screening them ment and follow-up therapy to address his serious for antianxiety properties. He screened 19 out of 20 dependence. compounds with no success, and moved on. Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER SIX The Age of Anxiety 131 As the story goes (Snyder, 1996), a year and a effective in reducing anxiety-related symptoms in half later, while cleaning his lab, he found the 20th 70 to 80% of people. This result must be considered compound and decided to have it screened. It in light of the fact that the symptoms vary consid- turned out quite active. The final steps of its syn- erably across time and go into remission with a pla- thesis completely altered its chemical properties cebo in 25 to 30% of clients. Benzodiazepines also from a quinazoline to what we now call a benzodi- serve as sedatives, muscle relaxants, intravenous azepine. The first benzodiazepine chlordiazepoxide/ anesthetics, and anticonvulsants. Librium was patented in 1959 and marketed as Lib- rium in 1960. Research continued, and diazepam/ Varieties of Benzodiazepine Compounds Valium was released in 1963. Currently, 15 benzo- diazepines (12 of which are commercially available The five families or subclasses of benzodiazepines vary in the United States) are on the market and listed in in potency, duration of action, and amount of time Table 6.3 (Julien et al., 2011). Benzodiazepines are they take to clear out of the body. The older com- pounds rely more heavily on the liver for metabolism. TABLE 6.3 Examples of Benzodiazepines The more drug metabolism relies on the liver, the more the drug induces moderate metabolic tolerance. The names of the five families of benzodiazepines are Mean Elimination Half-life (Range related to their chemical properties. Brand Name Generic Name in Hours) 2-Keto Compounds Valium Diazepam 20–50 Of the three types, 2-keto benzodiazepines are the old- Librium Chlordiazepoxide 50–100 est and most lipophilicitous. These compounds are oxidized primarily in the liver, a relatively slow process. Dalmane Flurazepam 70–160 As a result, these benzodiazepine compounds have the longest elimination half-lives (up to 60 hours). Many Paxipam Halazepam 10–20 have multiple active metabolites, so it takes the body Centrax Prazepam 30–200 longer to clear them out of the system. An example of a 2-keto compound is diazepam/Valium. Diazepam/ Tranxene Chlorazepate 20–170 Valium (like many 2-keto compounds) is a prodrug, Ativan Lorazepam 10–24 meaning (as noted earlier) it actually enters the body relatively inactive and becomes active as the body Klonopin Clonazepam 18–50 begins to metabolize it. The initial compound (diaze- pam) acts as a precursor for methyldiazepam, which is Ativan Lorazepam 15 further metabolized to oxazepam/Serax. The 2-keto Dormalin Quazepam 25–50 compounds are more likely to induce tolerance and dependence because of their potency. Because people ProSom Estazolam 13–35 taking these compounds still have active metabolites in Versed Midazolam 1.5–4.5 their urine, pharmaceutical companies found they could synthesize less-potent compounds that would Serax Oxazepam 5–15 clear more quickly and still produce the desired anxio- lytic effects. Restoril Temazepam 8–35 Halcion Triazolam 1.5–5 7-Nitro Compounds 7-Nitro compounds (e.g., clonazepam/Klonopin) Xanax Alprazolam 11–18 typically have shorter half-lives but by no means © Cengage Learning® the shortest. As you can see from the overview of Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 132 PART TWO Introduction clonazepam/Klonopin in Table 6.3, the half-life is have no active metabolites and thus are excreted 18–30 hours—short compared to chlordiazepoxide/ more quickly. The rest are metabolized first into Librium but quite long compared to midazolam/ active metabolites and then are further metabo- Versed. lized, taking longer to excrete from the body. Benzodiazepines come in parenteral and oral 3-Hydroxy Compounds formulations. The 3-hydroxy compounds are also metabolized through the liver, as well as through direct joining Mechanisms of Action with endogenous compounds, which brings about Research continues to shed new light on mechan- more rapid oxidation (negative charging and water isms of action (summarized in Table 6.4) in the ben- solubility) and thus a shorter half-life (10 to 15 zodiazepines. First and foremost, benzodiazepines are hours). Examples of 3-hydroxy compound benzo- pure GABA agonists because they facilitate GABA diazepines include oxazepam/Serax, lorazepam/ binding at GABA receptors. GABA is 200–1000 Ativan, and temazepam/Restoril. Although less times more abundant in the brain (depending on likely to induce tolerance and dependence than the which part of the brain you study) than other neu- 2-keto compounds, these medications still possess rotransmitters like serotonin and acetylcholine. The these drawbacks and should not be used for long- GABA binding facilitated by benzodiazepines then term treatment of symptoms. leads to opening of chloride channels, which further hyperpolarizes neurons (remember that chloride is a Triazolo Compounds negatively charged ion) (Dell’osso & Lader, 2013; The triazolo benzodiazepine compounds are very Wafford & Ebert, 2006). There are two types of similar to the 3-hydroxy compounds. They are GABA receptors in the brain; GABAa and more quickly oxidized, rely less on the liver to metab- GABAb. GABAa is the target of benzodiazepine olize, and leave f