Help Needed

Please see attached. 

Week3

Respond to the following in a minimum of 175 words: 

 Anxiety disorders are the most prevalent mental health conditions. Although they are less visible than schizophrenia, depression, and bipolar disorder, they can be just as disabling. 

What are some of the differences between developmental theories of anxiety and cognitive theories?

Which theory do you believe has the most validity? Why?

Based, on research findings what is the most effective treatment for anxiety related disorders? Why?

CHAPTER SIX
The Age of Anxiety

The multiple perspectives we have been using in this book are particularly useful in understanding the impact anxiety has on U.S. society. The word “anxiety” comes from a Latin root meaning to “choke or throttle” connoting a troubled state of mind (Tone, 2009). Anxiety disorders are believed to be the most common mental health problem in the United States. Two common measures are lifetime morbid risk (the theoretical risk of getting a disorder at any point in life) and 12-month prevalence (the proportion of the population thought to suffer from the disorder in any 12-month period). Baxter et al. (2013) conducted a meta-analysis of 87 studies from 44 countries between 1980 and 2009. They found that anxiety disorders are common across the globe with an estimated current prevalence of approximately as much as 28% of the global population. The prevalence of anxiety disorders in the United States is estimated for lifetime morbid risk/12-month prevalence as follows: Specific Phobia 18.4%/12.1%, Social Anxiety Disorder 13%/7.4%, Post Traumatic Stress Disorder (PTSD) 10.1%/3.7%, Generalized Anxiety Disorder 9%/2%, Separation Anxiety Disorder 8.7% /1.2%, and Panic Disorder, 6.8%/2.4%, (Kessler, Petukhova, Sampson, Zaslovsky, & Wittchen, 2012). Although anxiety disorders are prominent, it is important to realize that their incidence has remained steady over several decades despite pharmaceutically funded efforts to make the public think there is an epidemic that needs medicated (Baxter et al., 2014).

Although psychotropic medications are available for anxiety disorders, many psychological treatments also have excellent track records. Remember, from an integrative perspective it is not enough to describe anxiety symptoms, posit a biological explanation, then describe how certain drugs act biologically to (at least temporarily) decrease or eliminate these symptoms. With sentient beings, we have to look to the psychological, cultural and social variables that contribute to anxiety.

We recall a client (Elijah) who lived in what could be described as a 

“toxic environment.”

 Elijah’s urban residence was the regular scene of violence, and he himself had witnessed two shootings in his 23 years. He was court-ordered to receive treatment for an alcohol-related charge (drunk and disorderly conduct). Even after abstaining from all drugs for 60 days, Elijah was what could only be described as “a nervous wreck.” He showed symptoms of both Panic Disorder and PTSD (the latter related to stimuli associated with the shootings he had witnessed). In consultation with a psychiatrist, who prescribed SSRI medication, Elijah asked why he had his symptoms, and the doctor replied, “Some people have a genetic predisposition to such things.” As Charlie Brown would say, “Good grief!” In this client’s case, genetic predisposition not withstanding, there were clearly psychological, cultural, and social contributors to his anxiety. His alcohol use was a classic example of self-medication. Although the SSRI medication provided a window of opportunity for Elijah, it was going to take far more to alleviate his anxiety. Tragically, Elijah was stabbed in a fight at his residence, and although he recovered from that, he never re-entered treatment. As we have urged in previous chapters, mental health professionals must not lose sight of clients like Elijah nor surrender them to the partial truths of medical model explanations.

Although society has effective psychological interventions for anxiety, researchers estimate that only 30% of people suffering from an 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 so much anxiety in this population? It is not enough for mental health professionals to treat clients and refer them for psychiatric consultations. From an integrative perspective, we must wrestle with the question of why there are so many anxious people. Although moderate alcohol use can be perfectly appropriate, mental health professionals need to ask why there is so much abuse of alcohol in Western societies. When reflecting on cases like Elijah’s, therapists must also remember that anxiety symptoms are just as prominent in people living in nontoxic environments. What are people so anxious about, and is medication really the best solution? Although mental health clinicians must know about medications that can provide relief for clients, they must also address these broader questions.

This chapter is divided into eight sections. Section One provides an overview of anxiolytic medications and the construct of anxiety. Section Two focuses on areas of the central nervous system pertinent to anxiety and its treatment. Section Three covers central nervous system depressants including barbiturates and benzodiazepines. Section Four covers nonbenzodiazepine alternatives in treating anxiety. Section Five introduces newer approaches to treating anxiety. Section Six covers antidepressants used as anxiolytics. Section Seven summarizes anxiolytic therapy by diagnosis and Section Eight returns to important psychological, cultural, and social considerations.

SECTION ONE: OVERVIEW OF ANXIOLYTIC MEDICATION AND THE CONSTRUCT OF ANXIETY

Learning Objective

s

• Understand that there is a wide variety of anxiolytic drugs.

• Have a working definition of anxiety.

Thirty years ago, we would probably have titled this entire chapter “Central Nervous System (CNS) Depressants,” because those were the primary compounds available for treating anxiety. Currently, psychotropic medications from numerous classes are used to treat anxiety symptoms, including CNS depressants, SSRI antidepressants, and unique compounds such as buspirone (BuSpar). There is currently research being done on developing different benzodiazepines (Trincavelli, Da Pozzo, Daniele, & Martini, 2012), anxiolytics from antibiotics (Johnstone et al., 2004) and from neurosteroids (Nothdurfter et al., 2011). In addition, more studies are examining melotonin (Ochoa-Sanchez et al., 2012) and kava (Alramadhan et al., 2012), which we discuss further in the chapter on herbaceuticals. In general, anxiolytics are the most commonly used psychotropic medications and general practitioners (nonpsychiatrists) prescribe the vast majority (less than 20% are prescribed by psychiatrists). This situation required us to structure this chapter differently from the others in this book. For this chapter, we begin with a general discussion of anxiety, then describe anxiety from the medical model perspective, and then describe the different classes of drugs for anxiety. In discussing each class of drugs, we outline some of the drug’s history; mechanisms of action; side effects; and potential for tolerance, dependence, and overdose. Finally, we outline recommended pharmacologic approaches as well as other treatments for particular anxiety disorders from DSM-5. The treatment of anxiety in children and adolescents will be covered in a later chapter.

The Construct of Anxiety

Anxiety, in and of itself, is natural and adaptive. A moderate amount of anxiety enhances physical and intellectual performance. This is reflected in what is called the Yerkes-Dodson law (Yerkes & Dodson, 1908). Simply stated, it means people perform a little better when they are slightly anxious, but too much anxiety tends to impair performance and too little leaves them unmotivated to do their best (Barlow & Durand, 2002). You may have been initially anxious picking up this book. If you were moderately anxious, the anxiety likely helped you motivate yourself to get to this chapter. Readers who felt crippled with anxiety reading 

Chapter One

 probably didn’t get this far.

Anxiety was instrumental in the birth of psychoanalysis and psychodynamic models of the mind. In Inhibitions, Symptoms, and Anxiety (Freud, 1925), Freud unfolded his thinking about anxiety and its relationship to the structural model of the mind: id, ego, and superego. In this seminal work, he developed the notion of anxiety neurosis and identified two forms. The first was a sense of worry or dread that originated in a repressed wish or thought that generated conscious and unconscious conflict and was curable through the psychological treatment he developed into psychoanalysis. The second was an overwhelming sense of panic, accompanied by autonomic nervous system arousal (sweating, increased heart rate, and diarrhea). This, he thought, resulted from a buildup of libido and required a sexual outlet. Freud viewed anxiety as a result of conflict between unconscious sexual or aggressive wishes in the id and the corresponding punishment (or threat of punishment) from the superego. Anxiety is thus seen as a signal of danger in the unconscious, which could then result in a dangerous behavior or in inhibition. In response to the signal, the ego mobilizes defense mechanisms to prevent unacceptable feelings from emerging into consciousness. If the signal fails, the anxiety just keeps getting more intense and becomes immobilizing.

As you can see from this summary, although his explanations were mostly wrong, Freud was correct in differentiating panic from anxiety and would not be the last to do so. Anxiety is often differentiated from panic and fear. Anxiety is defined as a future-oriented, negative mood state characterized by bodily symptoms of physical tension and by apprehension about the future. A key feature of the apprehension is related to the sense that the person cannot control upcoming events (Barlow & Durand, 2002). Anxiety itself can be seen in the 11 Anxiety Disorders listed in the DSM-5, in several of the Personality Disorders (Histrionic, Dependent, and Obsessive-Compulsive), Delirium, Delusional Disorder, Major Depressive Disorder, and Schizophrenia. Anxiety Disorders are commonly comorbid with Substance Use Disorders (Wolitsky-Taylor, Operskalski, Ries, Craske, & Roy-Byrne, 2011). Fear is an immediate alarm reaction to danger and is characterized by autonomic nervous system stimulation (e.g., increased heart rate and respiration). The autonomic nervous system stimulation is thought to help the person escape the feared stimulus. Panic, in contrast, is an abrupt onset of intense fear, usually accompanied by physical symptoms such as heart palpitations, shortness of breath, and dizziness. Barlow and Durand (2002) described panic as a fear response when there is nothing (apparently) to be afraid of (in other words, a false alarm).

The Case of Marcia

Marcia, a 36-year-old female teacher, married with two adolescent teenagers, has struggled with mental and emotional issues for the past 11 years. She has been diagnosed with (not at the same time) Major Depressive Disorder, Dysthymic Disorder, Seasonal Affective Disorder, Avoidant Personality Disorder, and Personality Disorder Not Otherwise Specified (NOS). During the course of her treatment, Marcia was a very compliant patient. She always took her medications, mostly TCAs, and seldom missed therapy sessions. During the 11 years of her treatment, she had cognitive-behavioral therapy with a feminist female therapist, gestalt therapy with a male therapist, and holistic therapy with another female, and she tried various workshops and techniques such as art therapy. Almost always, the intervention or theoretical approach was combined with a psycho-tropic medication. Marcia improved slightly, only to return to what appeared to be a depressed and irritable state.

In the 10th year, after much frustration, Marcia was referred to a psychoanalytically oriented psychotherapist who spent several sessions with her conducting an assessment. After this thorough and extensive evaluation period, he made the diagnosis of Generalized Anxiety Disorder (GAD) and began to speak with her about the ways anxiety and panic manifested in her life. She seemed to talk about being incurably worried, exhausted, and never able to relax. Marcia existed in a state of agitation. They also discovered together that the closer Marcia got to a performance, a test in graduate school, giving a party, or being at a party, the more she panicked and fretted. The therapist referred her to a psychiatrist for assessment for medications and she prescribed clorazepate/

Tranxene

for her anxious conditions. The combination of insight therapy and clorazepate/Tranxene was very beneficial. Marcia gradually decreased her irritability, learned more about the triggers and pressures on her life from inside herself, and appeared less depressed.

In the first session, Marcia said three things that helped the therapist clarify his diagnosis: (1) “As I get closer to an obligation or performance, I begin to worry, ruminate, fret, and feel totally overwhelmed”; (2) “I fight these terrible battles within 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 something else, not depression.” Thus, from her own words and her various therapeutic journeys, it is evident that Marcia had a strong personal hunch that her previous diagnoses and treatments were not quite accurate. (We might say her intra-psychic intuition was working fine.) Marcia was most helped by a dynamic psychotherapy and a benzodiazepine, clorazepate/Tranxene. Although we have not delved into the social and cultural influences in Marcia’s case, it illustrates a very common error in current diagnostic thinking, namely that many anxiety symptoms often get subsumed in a diagnosis of depression (as mentioned in 

Chapter Three

). It is true that Marcia did get depressed and exhibited depressive symptoms, but her primary problem was anxiety, showing the importance of thorough diagnosis before any referral for medication.

THEORIES OF ANXIOLYTIC ACTION

As with depression, theories of anxiety rooted in the medical model hypothesize that some physiological process is deficient or impaired and that this deficiency or impairment results in a person having anxiety. Although some research supports this hypothesis, it is far from conclusive. As noted at the beginning of this chapter, there are more successful psychosocial interventions for anxiety than any other category of disorders. If anxiety were due solely to a physiological problem, why would psychological interventions be so successful? Even the most rigorous medical model theory of anxiety cannot dismiss the importance of the mind and of the type of knowledge available from a psychological perspective.

Review Question

s

• What are some general types of anxiolytic drugs?

• What is your working definition of anxiety?

SECTION TWO: THE CENTRAL NERVOUS SYSTEM: ANXIETY, BRAIN CIRCUITS, BRAIN STRUCTURES, AND NEUROTRANSMITTERS

Learning Objectives

• Understand the role of the Behavioral Inhibition System in Anxiety.

• Be able to articulate what neurotransmitter systems seem to be important in treating anxiety.

In earlier chapters, we have described several brain structures and some of the neurotransmitters in the brain associated with the types of symptoms psychotropic medications are designed to treat. In this section, we return to this topic to summarize the more popular medical model explanations of anxiety. A primary brain circuit associated with anxiety is called the behavioral inhibition system (BIS) (Baskin-Somers, Wallace, MacCoon, Curtin, & Newman, 2010; Gray, 1987; McNaughton & Gray, 2000). This circuit leads from the limbic system to the frontal cortex and is triggered from the brain stem. In the limbic system, meaning attaches to incoming stimuli and the frontal cortex processes executive functions. The circuit is triggered by things such as unexpected events that act as signals for danger; for example, abrupt changes in bodily functioning or visual stimuli. In abrupt changes in body functioning, the signals arise from the brain stem, and in changes in visual stimuli they descend from the cortex. Either way, BIS activation leads the person to freeze, experience anxiety, and evaluate the situation for danger (Keough & O’Conner, 2014).

This brain circuit is hypothesized to underlie the type of anxiety seen in GAD (Maack, Tull, & Gratz, 2012) and creates effects that differ from the “fight or flight” circuit. The fight-or-flight circuit originates in the brain stem (associated with vital body processes such as heart rate and respiration) and proceeds through several limbic system structures. Stimulating this circuit produces an “alarm and escape response” that researchers believe manifests as panic such as that seen in Panic Disorder. In the panic response, the limbic system, hypothalamus, and pituitary gland release a cascade of neurotransmitters and hormones that prepare the body for action. Markarian, Pickett, Deveson, and Kanona (2013) have also noted that the BIS can trigger anxiety when “… decreased responsiveness to rewards and a heightened sensitivity to aversive stimuli may predispose for difficulties regulating emotions” (p. 285) suggesting a role for the BIS in personality disorders.

A Hypothesized Braking System

Preston et al. (2002) note that the brain does have a “brake system” of sorts. This brake system consists of the ion channels on most neurotransmitters that allow negative ions (particularly chloride) to flow into the neuron to decrease its excitability. Researchers hypothesize that an as-yet-undiscovered endogenous benzodiazepine molecule binds with receptors to allow this influx of chloride ions. The hypothesis basically states that a deficiency of this yet-to-be-discovered substance causes anxiety disorders. Like the amine theory of antidepressant action, this hypothesis is a convenient extrapolation from the minimal data available on these brain circuits but is hardly convincing when you consider all the environmental and psychological factors that can trigger anxiety. Much research on anxiety and brain structures points to action in the amygdalae. The amygdalae are almond-shaped structures (one on each side of the brain) in the limbic system that are involved in how we attach emotional meaning to incoming stimuli. Advokat, Comaty, and Julien (2014) have summarized research showing that electrical lesions of the amygdala result in an anxiolytic effect as well as research documenting amygdala abnormalities in patients with Panic Disorder. The latter two examples have a “chicken-and-egg” problem. Miller, Piasecki, Peabody, and Lonstein (2010) found that antagonism of GABAa in anxiety-resistant rats increased anxiety. GABA is a neurotransmitter that tends to function in the brain to calm the organism. As noted, although this research certainly supports the hypothesis that the amygdala plays a role in anxiety symptoms, it does not confirm that defects in the amygdala cause anxiety symptoms.

Neurotransmitters Involved in Anxiety

GABA has clearly been indicated as playing a role in relief from anxiety in that facilitation of GABA binding is one mechanism that decreases anxiety. For example, benzodiazepines facilitate the binding of GABA to GABA receptors but do not directly stimulate GABA. By binding to an adjacent receptor, they change the shape of the GABA receptor making it more receptive to GABA molecules. Less well understood are the roles of serotonin and norepinephrine. Currently, some medications prescribed for anxiety target either serotonin (e.g., SSRI antidepressants) and/or norepinephrine. Perhaps it is easier to understand how norepinephrine is involved in anxiety, because the fight-or-flight circuit includes large releases of norepinephrine via the locus coeruleus. The locus coeruleus (“blue disk”) is a small brain structure (estimated to be about 10,000 neurons) whose neurons project to most other norepinephrine neurons in the brain. This structure can trigger the release of norepinephrine, stimulating the sympathetic nervous system, resulting in tachycardia, tremor, sweating, and anxiety. One medication (clonidine/Catapres) paradoxically treats such stimulation by releasing norepinephrine as an alpha adrenergic receptor agonist, and this fools the brain into thinking the NE levels are higher than they really are and thus overall lowering NE levels. Although this medication successfully reduces physiological symptoms associated with noradrenergic overactivity, it does not relieve the psychological aspects of anxiety.

Another neurotransmitter implicated in anxiety is serotonin. Although its role is still unclear, apparently several serotonin agonists are helpful with anxiety. One theory is that the brain structures implicated in fear and anxiety (the hippocampus, amygdala, septum, and dorsal raphe nucleus) are rich in 5-HT1a receptors. In animal models, mice bred without these receptors have heightened fear responses (Rambos et al., 1998) so the fact that SSRI drugs activated them through reuptake inhibition is thought to account for their anxiolytic quality in some clients.

In the last 20 years, researchers have made numerous advances in conceptualizing and treating anxiety disorders. Some may argue that the anxiety disorders are so heterogeneous that it is not accurate to include them all under one category, and there is much to support this assertion. DSM-5 redesigned the anxiety disorder so that Obsessive Compulsive Disorder and PTSD were moved out of Anxiety Disorders and into their own categories (Obsessive Compulsive and related Disorders and Trauma and Stressor Related Disorders respectively) (APA, 2013).

Review Questions

• What is the role of the Behavioral Inhibition System?

• What neurotransmitter systems seem important in the treatment of anxiety disorders?

SECTION THREE: CENTRAL NERVOUS SYSTEM DEPRESSANTS

Learning Objectives

• Be able to state the differences between an anxiolytic and a hypnotic.

• Know what the mechanisms of action are for barbiturates and benzodiazepines.

• Be able to list the advantages of benzodiazepines over barbiturates including the risks of overdose and addiction.

• Understand how the early anxiolytics like meprobemate became the first celebrity psychotropics.

Central nervous system depressants are a group of medications with diverse chemical structures that induce behavioral depression. They produce many effects ranging from relief from anxiety and inhibitions, to inducing relaxation and sleep, to inducing unconsciousness, general anesthesia, and (in overdose) coma and death. The predominant tendency of all these drugs is to inhibit the excitability of neurons.

Unfortunately, several terms are used to refer to CNS depressants, including sedatives, tranquilizers, hypnotics, and anxiolytics, which can cause confusion when you are first learning this material. In the first half of the 20th century, anxiety was not a common construct and most patients were medicated with “sedatives” for “anxiety neuroses.” These sedatives were usually 

bromides

 or barbiturates combined with everything from cannabis to digitalis. With refined diagnostic criteria, therapists would now say that many of these cases of “nerves” were actually depression and would be more likely to treat them with compounds described in 

Chapter Five

 (Healy, 2002).

The inducement of sleep is referred to as a “hypnotic effect.” This is inaccurate, because sleep induction is actually very different from what happens (or doesn’t happen) in hypnosis, but the term was coined at a time when people believed hypnosis induced a sleeplike trance. 

Anxiolytics

 are drugs used for treating anxiety. We prefer the term anxiolytic throughout this book. The inaccurate phrase “minor tranquilizers” is often used for anxiolytics but indicates only that these drugs treat milder symptoms than those treated by drugs labeled “major tranquilizers.” As you will see in 

Chapter Seven

, the phrase “major tranquilizer” is also sometimes misapplied to certain types of antipsychotic medication. So many poorly chosen words! At this point, the reader may conclude that the field of psychopharmacology could benefit from the services of a grammarian. Although we want readers to be familiar with all these terms, we encourage the use of the more accurate terms “anxiolytics” and “hypnotics.” Anxiolytics are for decreasing anxiety and hypnotics are for inducing sleep. Next we discuss the CNS depressants that are currently (or historically have been) used to treat anxiety.

Barbiturates

The first barbiturates were created in the late 19th century and introduced to the United States in 1912, the first being phenobarbital. According to Julien et al. (2011) between 1912 and 1950, hundreds of barbiturates were tested and at least 50 were marketed. Although these medications are rarely used for anxiety now, they dominated the antianxiety market until about 1960, when their dangers and drawbacks became widely known. We discuss barbiturates in this book not so much because they are often used but because their undesirable qualities set the baseline for desirable qualities researchers wanted in the anxiolytic drugs they were trying to develop and that currently dominate the market. As Stahl (2000) points out, barbiturates do not really have a specific anxiolytic effect but merely reduce anxiety as a side effect of their overall sedating effects, much like drinking too much whisky might.

The name “barbiturate” is said to have been chosen either because the urine of a girl named Barbara was used to derive the compound or because it was synthesized on St. Barbara’s Day (Snyder, 1996). For the curious minded, St. Barbara’s Day is December 4 and she is the patroness of miners (and perhaps barbiturate users, for all we know). She was martyred in C.E. 235 or 238. As far as using urine to synthesize compounds is concerned, the curious minded might also wonder what that is about. The answer is, as mentioned earlier, that drug companies examine the urine of subjects taking medications, to check for active metabolites of the drug. These active metabolites then provide the blueprint for synthesizing the compound or similar compounds. Barbiturates are derived from a parent compound barbituric acid that was first synthesized in 1864. It was marketed in the United States as Veronal in 1903 and because of loose guidelines governing pharmacy practice became a popular street drug known as “goofballs” or “the poor man’s psychoanalysis” (Tone, 2009). There was also a combining of barbiturates with beer into a deadly concoction called a “Wild Geronimo” (Rasmussen, 2009).

Barbiturates have rapidly become the dinosaurs of drugs. As anxiolytics, they have been displaced by benzodiazepines. The effects of barbiturates are quite similar to those of alcohol, and their main advantage is that they are cheap because their patents have expired (although this is not really an advantage because most benzodiazepines are generic as well). Barbiturates differ from each other primarily in terms of how quickly they act and in the intensity and duration of their action. Half-lives range from three minutes to several days. The differences in these properties are the main consideration in deciding which barbiturate to use. The clinical use of these has declined because they are lethal in overdose, the therapeutic dose can be close to a toxic dose, they induce tolerance and dependence, and they interact dangerously with other drugs (Advokat et al., 2014).

Mechanisms of Action

Researchers once believed barbiturates caused a general decrease in neuron excitability throughout the nervous system. They believed the dominant action was to hyperpolarize many types of neurons (recall that “to hyperpolarize” means to increase the probability that a neuron will not fire). As with reality, the truth appears more complex than that. In 

Chapter Two

, we wrote that glutamate tends to be a generally excitatory neurotransmitter and that GABA is generally an inhibitory neurotransmitter. Initial evidence in the late 20th century was that barbiturates may act as glutamate antagonists (Zhu, Cottrell, & Kass, 1997), as well as GABA agonists (Tomlin, Jenkins, Lieb, & Franks, 1999). Although there are still aspects of barbiturate action we do not understand, the primary mechanisms seem to be these. First barbiturates act to prolong and potentiate the actions of GABA. At higher doses, they bind to GABAa receptors acting directly on them. When a drug allows an influx of negatively charged ions into the neurons, it hyperpolarizes the neurons, decreasing the probability that they will fire. Barbiturates also block AMPA/kainite receptors (glutamate receptors) decreasing the excitability of neurons (Loscher & Rogawski, 2012). In addition to facilitating the binding of GABA, barbiturates allow the influx of chloride, a negatively charged ion, into the neurons. This effect accounts for the increased toxicity of barbiturates compared to benzodiazepines (Advokat et al., 2014). 

Table 6.1

 summarizes these hypothesized mechanisms of action in barbiturates. You can imagine that combining all these mechanisms of action would have a potent inhibiting effect on the nervous system.

The neurons in the reticular activating system (RAS) are particularly sensitive to barbiturate drugs. The RAS is involved in sleep, and this is one reason why barbiturates have a hypnotic effect. In addition, sites of action include the cerebellar 

pyramidal cells

 (involved in fine movement), the substantia nigra (motor skills), and the thalamus (processing sensory information). Barbiturate action on these brain structures results in loss of coordination (ataxia), which increases with dosage. In terms of pharmaco-kinetics, barbiturates are rapidly absorbed and distributed to most body tissues. The ultra-short-acting barbiturates are lipid soluble, cross the blood–brain barrier quickly, and can induce sleep in seconds. As noted, barbiturates differ in their length of action. 

Table 6.2

 lists commonly used barbiturates, duration of effect, and common uses.

TABLE 6.1 Hypothesized Mechanisms of Action in Barbiturate Medications

Action	Result
First-messenger binding	Facilitates the actions of to GABA receptors (acts as a GABA agonist) at those receptor sites, decreasing neuronal activity
Antagonism of glutamate	Decreases neuronal activity
Facilitation of chloride conductance into neurons	Further hyperpolarizes neurons

© Cengage Learning®

Common Side Effects

Common side effects for barbiturates include behavioral depression, sleepiness and particularly disruption of REM sleep, motor and cognitive inhibition similar to those seen with alcohol, ataxia (loss of muscle coordination), and respiratory depression. Barbiturates are contraindicated in people with severe respiratory disease or liver impairment, or who are concomitantly using other CNS depressants. They are clearly contraindicated for people who may be experiencing suicidal ideation, because the drugs are so easy to overdose on.

Tolerance and Dependence

Barbiturates can induce both physical and psychological tolerance and dependence. Physical tolerance occurs via metabolic and cellular mechanisms. Metabolic tolerance is caused by an increase in the enzymes that metabolize barbiturates, resulting in a need for higher and higher doses. Cellular tolerance is the condition of the neurons adapting to the presence of the drug. Physical dependence is usually manifested by sleep difficulties when withdrawing from barbiturates, but withdrawal from high doses may also be accompanied by hallucinations and lethal convulsions (Advokat et al., 2014). The psychological dependence results from the anxiolytic action. Depending on the individual and on the set and setting of barbiturate administration, some people may experience a euphoric response that is also linked to psychological dependence. The phrase “set and setting” refers to the mind-set of the person taking the drug and the physical place and context (setting) where the person is taking a drug.

TABLE 6.2 Examples of Barbiturate Drugs, Their Duration of Effect, and Common Uses

Hypnotic

Name	Duration of Effect	Common Uses
Thiopental	15 minutes	Anesthetic
Secobarbital	30 minutes		Hypnotic
Pentobarbital	4 hours
Phenobarbital	6 hours	Anticonvulsant

© Cengage Learning®

Barbiturates and Overdose

Researchers estimate that barbiturates have been involved in nearly one third of drug-related deaths, including the deaths of several celebrities (Boston University Medical Center, 2002). Actresses Rachel Roberts and Carol Landis both committed suicide with barbiturates, and actresses Judy Garland and Marilyn Monroe are said to have died of barbiturate overdoses [although signs of overdose are still being disputed in Monroe’s case (DiMaggio, 2006)]. Although many of these deaths appear to be intentional suicides, others are accidental or possibly murders. The effects of barbiturates can be so disorienting that a person may take one dose and then a second or third, having forgotten the previous doses. The toxicity of barbiturates is also apparent in their approval as euthanasia agents for lab animals. Partly in response to the toxicity of barbiturates and to their multiple uses, pharmaceutical companies in the early to mid 20th century began to seek out nonbarbiturate alternatives with all the efficacy of barbiturates but without their toxicity and dangers.

The Case of Francis

In the late 1990s, Francis, a 42-year-old unmarried stock broker working in a high-powered investment firm, found himself increasingly tense, edgy, and agitated, which he expressed in an aggressive temper with coworkers and friends. He remembered that his father in his 40s had taken some sort of “-barbital” to help him calm down. He called his father, who even in his late 70s was very sharp. His father remembered that he had taken pentobarbital/Nembutal and it was very helpful in low doses. He even remembered the physician who had prescribed the medication and encouraged Francis to give him a call, because he was a friend and still in practice. Francis did, and the doctor, simply basing his decision on how helpful pentobarbital had been for his father, prescribed it for Francis. Francis did not seek assistance from therapy or a psychiatrist.

Francis began to use the sedative medication and found it very helpful. In fact, as time went on, he felt he needed more and more to get into the same calm and soothing state. He slept longer and deeper, but found waking up very difficult. Even though his physician warned him, Francis continued to need an ever greater supply of pentobarbital/Nembutal. Colleagues and friends began to worry about Francis’s unpredictable behavior, his barbiturate-induced stupors, and his impaired decision-making skills. Francis continued to deteriorate until one day he didn’t come to work, nor did he call. One of his worried colleagues went to his home and found him in a deep sleep. He noticed the bottle of pentobarbital/Nembutal and immediately called for help from an emergency medical technician (EMT). Francis was taken to a nearby emergency clinic, revived and treated, and released with a referral to a psychiatrist who specialized in anxiety disorders. He never followed up.

We have not yet addressed a psychological factor crucial to this case: Sometimes adult children who have overidentified with their parents seek out treatments that were helpful to their parents, even if those treatments are outdated. Francis kept himself outside the appropriate treatment nucleus and found treatment for his anxiety in exactly the same manner that his father had 20 years earlier—and it was not effective.

Nonbarbiturate Alternatives: Mother’s Little Helpers

The subtitle of this section, “Mother’s Little Helpers,” refers to the Rolling Stones song of the same name that was Keith Richards and Mick Jagger’s attempt to write a song that highlighted that drug problems are not confined to rock stars. The song is about a woman’s use of

Valium

to relieve the tedium of 1960s suburban life. Although Valium is a benzodiazepine, the benzodiazepine story begins with the search for nonbarbiturate alternatives to anxiolysis. The aim of nonbarbiturate alternatives was to make a drug that was safer but still reduced anxiety. Most of the nonbarbiturate alternatives were extremely similar to barbiturates in everything except molecular structure. Although each one was initially marketed with great fanfare as a safe alternative to barbiturates, most were equally dangerous and many were subsequently withdrawn from the market. The important result of research on nonbarbiturate alternatives is that it led to discovering the benzodiazepines, which we discuss shortly.

Meprobamate

In 1945, Czechoslovakian pharmacologist Frank Berger was attempting to develop antibacterial agents. In his research he stumbled onto a sedating compound that seemed to act like a barbiturate but did not induce sleep as readily. He noted it seemed to induce “tranquilization” without necessarily inducing sleep, and that term was used in marketing the new compound, to present it as different from barbiturates. The compound was marketed as meprobamate/Miltown in 1955 (Berger, 1970). Its primary success was that while reducing anxiety, it allowed people to remain awake. Like barbiturates, meprobemate/Miltown produced daytime sedation, relief from anxiety, and sometimes euphoria. Although not as toxic in overdose as barbiturates, meprobemate/Miltown seemed to induce tolerance and dependence to the same degree and appeared more teratogenic than barbiturates. Meprobamate is still prescribed under the trade names Miltown as well as Equanil.

Meprobamate/Miltown also signaled the beginning of the celebrity endorsement for drugs. Famous television star Milton Berle endorsed how well meprobemate/Miltown made him feel and that he took it. His frequent testimonials earned him the nickname “Uncle Miltown” by Time magazine in February of 1957. According to Andrea Tone’s research, in 1956 comedians made as many jokes about Miltown as they did about Elvis Presley (Tone, 2009, p. 65). Carter Wallace pharmaceuticals also commissioned artist Salvadore Dali to create a walk-though art work (“Crisalida”) that represented a person’s metamorphosis from the evils of nightmares to the divine dreams (all thanks to meprobemate/Miltown of course). By the mid-1960s, more people than ever were taking prescription anxiolytics.

It should be noted that Frank Berger, who developed meprobamate/Miltown in 1950, was a driving force against the popularization of medications in the media as well as the use of drug company representatives (called detail men in the 1950s) to educate physicians about medications. Because of the money he brought to Wallace Laboratories, he had enormous influence. Insisting that good sales pitch would never be good science, he insisted that no detail men be used and that only ads that are factual and educational should be released to doctors. This rule held until Berger retired in 1973 (Tone, 2009).

The Quaalude Years

Glutethimide/Doriden was introduced in 1954, and methaqualone/Quaalude in 1965. Both were hailed as nonbarbiturate alternatives but experience showed otherwise. In the 1970s and 1980s, methaqualone/Quaalude rivaled marijuana and alcohol in level of abuse in the United States. By 1972, the practice of mixing methaqualone/Quaalude with wine (“luding out”) was widespread across college campuses. Far from being nonbarbiturate alternatives, glutethimide/Doriden and methaqualone/Quaalude induced tolerance and dependence syndromes, and methaqualone/Quaalude overdose proved even harder to treat than barbiturate overdose. Methaqualone/Quaalude was linked to numerous deaths, so it was banned from the U.S. market in 1984. When taken off the market, methaphalone/Quaalude was placed on federal drug Schedule I, glutethimide/Doriden was placed on Schedule II because of overdose deaths. Federal drug schedules are really a listing on five levels of drugs considered least to most dangerous. Schedule I is for drugs that are illicit and supposedly have no medical uses although, as we will discuss later, this classification is debatable. As with barbiturates, euphoria associated with methaqualone/Quaalude seemed dependent on the set and setting of the drug user. In addition to these drugs, carisaprodal/Soma was introduced and is technically a precursor to meprobemate/Miltown. This is still used as a muscle relaxant in the 21st century. A final note, chloral hydrate/Notec, which was synthesized in the 1800s, is still abused as a CNS depressant which when combined with alcohol is abused as a “date-rape” drug (sometimes called a Mickey Finn) (Julien et al., 2011). These stories point out one pervasive problem in psychopharmacology: once the “genii” is out of the bottle (e.g., a drug is out on the market) it is almost impossible to put it back even though it may be criminalized.

The Case of John

John, a 36-year-old waiter, ex-con, and entrepreneur, was a product of the late 1960s and early 1970s. He believed one should be mellow at all times and should not become stressed under any circumstances. He was in a methadone treatment program to overcome his longstanding addiction to heroin. With the pressures of new marriage and a child, John felt he was becoming tense, agitated, and anxious. He visited his primary care doctor and told him about everything except the methadone treatment. After a brief assessment, the doctor prescribed methaqualone/Quaalude for John. The year was 1979, and given this drug’s street reputation John was pleased. He called it his “cool-down script.” Soon it seemed to others that the “ludes” became John’s substitute for his heroin addiction. He became a quasi-dealer for methaqualone/Quaalude and eventually became dependent on it. He deteriorated gradually but eventually lost his job and family as a result of this abuse/dependence. Fortunately, John had the inner resilience to request in-patient treatment and follow-up therapy to address his serious dependence.

Although scenarios such as John’s are not common today, clinicians recognize that in the history of developing pharmaceuticals for mental and emotional disorders some drugs, if abused, are very dangerous.

BENZODIAZEPINES

Benzodiazepines are the prototypic anxiolytic medications. Over the past 40 years, barbiturates were replaced by benzodiazepines, which are less dependence inducing and have less abuse potential. Benzodiazepines are still the leading treatment for anxiety (Dell’osso & Lader, 2013) and currently account for 90% of the anxiolytic market. In the United States, benzodiazepines are among the most prescribed drugs (Baldwin, 2012). In a recent meta-analysis, Dell’osso and Lader (2013) found the most common psychiatric disorders benzodiazepines were prescribed for included GAD, Obsessive Compulsive Disorder, Social Anxiety Disorder, PTSD, Panic Disorder, Agoraphobia (Panic Disorder and Agoraphobia are stand-alone disorders in DSM-5 as well as ICD-10), Sleep Disorders, Depressive Disorders, Alcohol Withdrawal (as a drug replacement strategy in Addiction Medicine), Delirium, Schizophrenia, and for side effects from neuroleptic medications (like haloperidol/Haldol or chlorpromazine/Thorazine). As you can see, they are used across a broad spectrum of disorders.

Some Anxiolytic History

Ever since Frank Berger had synthesized meprobamate, researchers had tried numerous combinations of muscle relaxers and sedatives to come up with an anxiolytic drug that would not totally sedate a person but would decrease anxiety significantly. Following up on research begun by Berger, Leo Sternbach, a Polish chemist working for Roche Drug Company in New Jersey, first synthesized chlordiazepoxide/

Librium

and diazepam/Valium. In trying to learn how meprobemate/Miltown acted at a molecular level, Sternbach and his colleague Earl Reeder were synthesizing chemicals called quinazolines and screening them for antianxiety properties. He screened 19 out of 20 compounds with no success, and moved on.

As the story goes (Snyder, 1996), a year and a half later, while cleaning his lab, he found the 20th compound and decided to have it screened. It turned out quite active. The final steps of its synthesis completely altered its chemical properties from a quinazoline to what we now call a benzodiazepine. The first benzodiazepine chlordiazepoxide/Librium was patented in 1959 and marketed as Librium in 1960. Research continued, and diazepam/Valium was released in 1963. Currently, 15 benzodiazepines (12 of which are commercially available in the United States) are on the market and listed in 

Table 6.3

 (Julien et al., 2011). Benzodiazepines are effective in reducing anxiety-related symptoms in 70 to 80% of people. This result must be considered in light of the fact that the symptoms vary considerably across time and go into remission with a placebo in 25 to 30% of clients. Benzodiazepines also serve as sedatives, muscle relaxants, intravenous anesthetics, and anticonvulsants.

TABLE 6.3 Examples of Benzodiazepines

Ativan

Lorazepam

Brand Name	Generic Name	Mean Elimination Half-life (Range in Hours)
Valium	Diazepam	20–50
Librium	Chlordiazepoxide	50–100
Dalmane	Flurazepam	70–160
Paxipam	Halazepam	10–20
Centrax	Prazepam	30–200
Tranxene	Chlorazepate	20–170
	Ativan		Lorazepam	10–24
Klonopin	Clonazepam	18–50
15
Dormalin	Quazepam	25–50
ProSom	Estazolam	13–35
Versed	Midazolam	1.5–4.5
Serax	Oxazepam	5–15
Restoril	Temazepam	8–35
Halcion	Triazolam	1.5–5
Xanax	Alprazolam	11–18

© Cengage Learning®

Varieties of Benzodiazepine Compounds

The five families or subclasses of benzodiazepines vary in potency, duration of action, and amount of time they take to clear out of the body. The older compounds rely more heavily on the liver for metabolism. 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 related to their chemical properties.

2-Keto Compounds

Of the three types, 2-keto benzodiazepines are the oldest and most lipophilicitous. These compounds are oxidized primarily in the liver, a relatively slow process. As a result, these benzodiazepine compounds have the longest elimination half-lives (up to 60 hours). Many have multiple active metabolites, so it takes the body longer to clear them out of the system. An example of a 2-keto compound is diazepam/Valium. Diazepam/Valium (like many 2-keto compounds) is a prodrug, meaning (as noted earlier) it actually enters the body relatively inactive and becomes active as the body begins to metabolize it. The initial compound (diazepam) acts as a precursor for methyldiazepam, which is further metabolized to oxazepam/Serax. The 2-keto compounds are more likely to induce tolerance and dependence because of their potency. Because people taking these compounds still have active metabolites in their urine, pharmaceutical companies found they could synthesize less-potent compounds that would clear more quickly and still produce the desired anxiolytic effects.

7-Nitro Compounds

7-Nitro compounds (e.g., clonazepam/Klonopin) typically have shorter half-lives but by no means the shortest. As you can see from the overview of clonazepam/Klonopin in Table 6.3, the half-life is 18–30 hours—short compared to chlordiazepoxide/Librium but quite long compared to midazolam/Versed.

3-Hydroxy Compounds

The 3-hydroxy compounds are also metabolized through the liver, as well as through direct joining with endogenous compounds, which brings about more rapid oxidation (negative charging and water solubility) and thus a shorter half-life (10 to 15 hours). Examples of 3-hydroxy compound benzodiazepines include oxazepam/Serax, lorazepam/Ativan, and temazepam/Restoril. Although less likely to induce tolerance and dependence than the 2-keto compounds, these medications still possess these drawbacks and should not be used for long-term treatment of symptoms.

Triazolo Compounds

The triazolo benzodiazepine compounds are very similar to the 3-hydroxy compounds. They are more quickly oxidized, rely less on the liver to metabolize, and leave fewer active metabolites in the system than do the hydroxy compounds. They also have short half-lives (15 hours). An example of a triazolo compound is alprazolam/Xanax. The triazolo compounds have been the most frequently prescribed benzodiazepines for anxiety since the late 20th century (Ballenger, 1995).

Imidazo Compounds

The imidazo compounds (midazolam/Versed) are short-acting benzodiazepines developed by HofmanLaRoche in the 1970s. They are used for seizures, insomnia, and inducing sedation and amnesia before surgical procedures. As can be seen from the overview of midazolam/Versed in Table 6.3, these compounds can have a half-life as short as 90 minutes. Imidazo compounds are more popular in veterinary medicine because of their water solubility.

Pharmacokinetics

All classes of benzodiazepines are well absorbed. The majority of shorter-acting benzodiazepines have no active metabolites and thus are excreted more quickly. The rest are metabolized first into active metabolites and then are further metabolized, taking longer to excrete from the body. Benzodiazepines come in parenteral and oral formulations.

Mechanisms of Action

Research continues to shed new light on mechanisms of action (summarized in 

Table 6.4

) in the benzodiazepines. First and foremost, benzodiazepines are pure GABA agonists because they facilitate GABA binding at GABA receptors. GABA is 200–1000 times more abundant in the brain (depending on which part of the brain you study) than other neurotransmitters like serotonin and acetylcholine. The GABA binding facilitated by benzodiazepines then leads to opening of chloride channels, which further hyperpolarizes neurons (remember that chloride is a negatively charged ion) (Dell’osso & Lader, 2013; Wafford & Ebert, 2006). There are two types of GABA receptors in the brain; GABAa and GABAb. GABAa is the target of benzodiazepine drugs. GABAb receptors are also implicated in anxiety. Basically when they are stimulated, they exert an inhibitory influence by decreasing the amount of potassium (“K” from the Latin Kalium) in the cell. Recall that potassium is excitatory and decreasing it would tend to inhibit the cells. A good example of a GABAb agonist is Baclofen, which is a derivative of GABA. Baclofen/Kemstro has been shown effective in treating anxiety in PTSD, Panic Disorder, and alcohol withdrawal (Vinkers, Crayn, Olivier, & Groenink, 2010).

TABLE 6.4 Mechanisms of Action of Benzodiazepines

Facilitate the binding of GABA through binding at a benzodiazepine receptor

Facilitate the flow of chloride into the neuron to decrease its excitability

Block stress-induced increases in NE, 5-HT, and DA

© Cengage Learning®

Side Effects

The side effects of benzodiazepines are dose related and are extensions of their therapeutic effects. The side effects include sedation, lethargy, ataxia, motor and cognitive impairments, slurred speech, and amnesia (depending on the benzodiazepine used). Side effects may also include respiratory suppression, depression, and in some cases a paradoxical excitation/agitation (Pies & Rogers, 2005). Note that unlike barbiturates, benzodiazepines do not appear to significantly disrupt REM sleep. They do however decrease REM sleep throughout the night and REM rebound is a possibility if a person is withdrawing from benzodiazepines (Greenblatt, 1991). Although they may disrupt deeper, delta-wave sleep, these effects are experienced as less troublesome than disruption of REM sleep. Specifically focusing on adverse effects Martin et al. (2007) summarized the following problematic side effects:

• Cognitive effects include impairment of learning, psychomotor slowing and anterograde amnesia (inability to create new memories after whatever caused the amnesia).

• Psychomotor effects include some evidence that (depending on the dose) benzodiazepines may impair driving ability.

• There is still controversy over whether benzodiazepines have teratogenic effects. The general consensus is that teratogenicity is low but some studies have illustrated a low correlation between benzodiazepines and cleft palate (see also Howland, 2009a).

• Some studies note subjects have a paradoxical reaction where after taking the drug they experience excitability. The disinhibitory effects (similar to alcohol) could produce increased aggression, anxiety, and hyperactivity.

• Special consideration is required before prescribing these to elderly clients as they are more sensitive to the effects of benzodiazepines. Over sedation can create a pseudodementia and some users may develop hangovers due to their sensitivity.

• Tolerance and dependence are still problems although the studies reviewed indicate that the majority of people taking benzodiazepines take them as prescribed (do not abuse them).

Tolerance and Dependence

Benzodiazepines can induce physical tolerance and both psychological and physical dependence. Although the benzodiazepines do not induce as much metabolic tolerance as barbiturates, they do increase production of hepatic drug-metabolizing enzymes (e.g., cytochrome P450 system). They also cause cellular tolerance in the form of down-regulation or decreased sensitivity of the receptors. Patterns of dependence can develop even at therapeutic dosages if continued over a long-enough period of time. If benzodiazepines are taken short term or infrequently (e.g., p.r.n., for Latin pro re nata, “as circumstances require”), clients generally do not develop tolerance to the therapeutic effects of the medications. As we have mentioned, although a great deal of hysteria surrounds the abuse of drugs with reinforcing properties, only a minority of clients on benzodiazepines abuse them. Some researchers have used patient databases to identify things like “doctor shopping,” which are highly correlated with abuse (Pradel, Delga, Rouby, Micallef, & Lapeyre-Mestre, 2010). The passage of laws to monitor prescriptions for drugs of abuse allow such patterns to be identified. In Ohio, where we work, there is an Ohio Reporting System (ORS) that is the state prescription monitoring program that is limited to health care professionals and law enforcement. There is still debate about the tension between things like the ORS database and confidentiality (Brushwood, 2003). When tolerance and dependence do occur, early withdrawal signs include insomnia, restlessness, and irritability, and the return of the anxiety for which the medication was being taken in the first place. The compounds with the highest affinity for receptors and the longest half-lives are more likely to induce tolerance and dependence. Most people taking benzodiazepines as prescribed do not develop tolerance but still experience the anxiolytic effects. Also note that any dependence that occurs is not associated with the types of craving experienced by people withdrawing from drugs such as cocaine or heroin. Acute benzodiazepine withdrawal lasts approximately 2–12 months but in some cases can last years at a lower grade level (Higgit, Lader, & Fonagy, 1985; Murphy & Tryer, 1991). It is hard to give concrete estimates because treatment depends on the type of benzodiazepine the client was taking. Short-acting benzodiazepines produce a more intense withdrawal than longer acting ones (Rickels, Schweizer, Case, & Greenblatt, 1991). Strategies to titrate clients down on the dosage of medication often result in craving and return to use so replacement and antagonist strategies are being developed (Hood, Norman, Hince, Meichar, & hulse, 2014).

Overdose Potential

Although the overdose potential of benzodiazepines is less than that of barbiturates, they are still toxic in overdose. Perry, Alexander, and Liskow (2006) report that doses of diazepam as high as 1355 milligrams have been reported without significant toxicity. Apparently when oral benzodiazepines are involved in overdoses, they are often only one of several substances ingested. Intravenous benzodiazepines, in contrast, have a high potential for toxic overdose, but of course the availability of these compounds is restricted. One of the more positive advances in this area is the development of a benzodiazepine antagonist (flumazenil). This compound binds to the same receptors as benzodiazepines but exerts no activity. It also competitively blocks these receptors, so it displaces benzodiazepines that have bound there. This drug can be used to treat a benzodiazepine overdose, although it may have to be injected multiple times, because its half-life is much shorter than the benzodiazepines it is intended to displace. In one 10-year review of benzodiazepine overdoses in adults treated with flumazenil, of the 904 cases treated, 13 developed seizures after administration and one death occurred. Although not a perfect record, many lives were saved with flumazenil that would have been lost without it (Kreshak, Cantrell, Clark, & Tomaszewski, 2012).

The Case of Jennifer

Jennifer, a 26-year-old ballet dancer, began to experience mild panic attacks prior to both rehearsal and performances. She developed powerful resistance to dancing, accompanied by tightness in her chest, rapid breathing, and sweaty palms. Until the recent attacks, Jennifer had been recognized as one of the premier young dancers in the ballet company. Now she could barely perform. The director of the company referred her to a panic/phobia specialist at a local teaching hospital. Jennifer went for an assessment and complete psychological and physical workup. As a result of the evaluation, he recommended group therapy and a regimen of prazepam/Centrax for Jennifer.

Jennifer expressed some reluctance to him about both treatments. She said her Eastern European culture frowned on sharing your deep personal problems in a group of people, and she was worried about the impact of the medication on her functioning and dancing. The psychiatrist addressed both issues (cultural and intrapsychic) with Jennifer and paid very close attention to her feelings about the panic and the treatment. Eventually Jennifer agreed to both treatments.

This treatment protocol was very successful for Jennifer. The prazepam gave her relief from her panic and agitation almost immediately and continued for her 12-week course of treatment. The 10-week group helped Jennifer talk about some of her fears and anxieties about professional dance, provided hope and support, and facilitated her catharsis with some rage issues that had been building in her. She was a willing and positive contributor to the group process, and she benefited from both treatment interventions.

We believe it is important to provide realistic cases about panic and anxiety with some that demonstrate improvement by the client. This well-designed treatment easily could have soured if Jennifer had become dependent on her prazepam and was not able to titrate off of it or if she had become overly dependent on her group.

The Case of Sherry

Sherry is a 46-year-old sexual abuse survivor with three children. She is divorced and works as an administrative assistant for a local accounting firm. Sherry has been in treatment on and off for over 20 years with several therapists and group approaches. Sherry has tried many medications during this time: TCAs, SSRIs, antipsychotics, antimanics, and more recently, a short-half-life benzodiazepine, alprazolam/Xanax.

Sherry reported that most medications helped her only for brief periods during the course of her treatment. Eventually all were either ineffective or caused her some discomfort because of side effects. Most recently, Sherry felt her therapy was going well. She reported less agitation, fewer intrusive memories of her abuse, almost no nightmares, and far less panic. She also reported improved relationship with her children, as well as comfort and success at work, and she began to date again. Sherry attributed her improvement to her twice-a-week therapy with an eclectic female therapist and her ability to take alprazolam/Xanax p.r.n. when she felt mounting agitation or anxiety in herself. She has learned to self-monitor these feelings, often derived from her chronic sexual abuse by her father between age 5 and 9. Sherry has learned in therapy that at certain times in her daily life she needs the help of alprazolam/Xanax. This occurs about once or twice a week, and Sherry believes the alprazolam/Xanax is very helpful at these times. Sherry has been using alprazolam in this way for three and a half years. She is not dependent on it and uses it very appropriately. Both Sherry and her therapist have begun to talk about what her life would be like without the alprazolam/Xanax.

We believe there are many varied uses for the benzodiazepines and that clients, therapists, and physicians can discover their uses by a careful understanding of the client and/or by applying an integrative framework to the case.

The Case of William

William, a 27-year-old, African American firefighter, developed panic attacks after a very serious fire. Almost immediately, the department physician prescribed diazepam/Valium for him, which he began taking. William did not like the drowsy, stuporous feeling from taking diazepam/Valium. In fact, after a week he became more agitated by the medication. His panic attacks worsened, and they got so intense that his supervisors recommended him for a disability leave because he could not function at work. William was distraught. He did not feel he had had an opportunity to talk with anyone about his panic and fears, and he detested the impact of the diazepam/Valium on him. Finally, William’s minister recommended to him an African American therapist at a neighborhood mental health center.

Certainly many factors influence this case. From the medical model perspective, William was speedily administered diazepam/Valium for his panic, with no evaluation or other considerations. From a psychological perspective, William certainly had a reaction to the medication, and it is possible to hypothesize from the information presented that he also may have been very reluctant to take it. From a cultural perspective, William is an African American, and he seems to trust the counsel of his minister about his mental health concerns first.

In considering the social perspective, a few issues loom. One could assume that diazepam/Valium was the benzodiazepine of choice by the fire department physician. Certainly many social forces are at work in recommending William for leave, including the potential stigma against firefighters with mental health problems. None of William’s spheres of experience or vantage points were explored in detail except by his minister.

William had several complex psychological issues that he discussed with his therapist. The first was his personal fear of medication, accompanied by a need to know more about the impact of the diazepam/Valium and its side effects. William was a Gulf War veteran, and elements of the fire that triggered his panic seemed reminiscent of some of the horrors he had witnessed in that war. Over a three-month therapy, William and his therapist worked on these issues, consulted with the staff psychiatrist, and developed a plan for him to return to work. Through some selective cognitive-behavioral therapy, William learned about his repressed fears by experiencing an all-engulfing fire that kills humans, and he gained some control over his panic. After a consult with the staff psychiatrist at the mental health center and a careful evaluation, they agreed to a course of oxazepam/Serax p.r.n. for times when William could not manage his growing panic. Oxazepam/Serax is from a different chemical family and is less potent than diazepam/Valium. The psychiatrist carefully explained all aspects of oxazepam/Serax to William and empowered him to take it only as needed. Together William and his therapist developed a strategy whereby he returned to work at full salary on “light” duty as a dispatcher, with the goal that he could request a return to regular duty. The minister initiated a treatment regimen that addressed William’s issues from an integrative perspective, and assisted in his recovery. The diazepam/Valium was not helpful, but the combination of oxazepam/Serax and therapy was.

Review Questions

• What is the primary difference between an anxiolytic and a hypnotic medication?

• What are the known mechanisms of action for barbiturates and benzodiazepines?

• What are the advantages of benzodiazepines over barbiturates including the potential for overdose and addiction?

• How did meprobemate/Miltown become the first “celebrity drug”?

SECTION FOUR: NONBENZODIAZEPINE ALTERNATIVES

Learning Objectives

• Be able to state how nonbenzodiazepines are similar to and dissimilar from benzodiazepines.

• Understand why buspirone may be a good medication for people recovering from drug or alcohol use problems.

• Be able to generally describe two new approaches to anxiolytic medications.

Researchers have made numerous efforts in recent years to synthesize some nonbenzodiazepine compounds that have the therapeutic effects of benzodiazepines without the possibility of tolerance and dependence. We discuss some of these and then newer research directions for anxiolytics.

HYPNOTICS

Hypnotics are classes of drugs that help you to sleep. Although these are structurally dissimilar from benzodiazepines, they bind to the same receptors as benzodiazepines and exert an agonist effect. Zolpidem/Ambien was marketed in 1993 as a short-term hypnotic. It is classified as an imidazopyridine which are GABAa receptor agonists. Chemically, it is structurally different from a benzodiazepine but acts in much the same manner. It binds at the benzodiazepine receptor but tends to induce sleep far more than providing a wakeful anxiolytic effect. Initially, it was believed that zolpidem did not induce tolerance and dependence with continuous use (Harrison & Keating, 2005). However, recent case studies and analyses contradict this (Chapla, Gallucci, Trimzi, & Meier, 2013; Zammit, 2009). There have been many clinical anecdotes about people “sleep binge eating,” “sleep driving,” and having rages under the influence of zolpidem/Ambien. One of the more famous was that of REM guitarist Peter Buck who was charged with attacking British Airlines staff and ransacking the first class cabin after ingesting zolpidem/Ambien with wine. Buck had no recollection of the incident and was cleared on the grounds that the medication induced the behavior and the amnesia (BBC News, 2002). In 2007, the FDA released a bulletin asking all manufacturers of hypnotics to strengthen their labeling to include the risk of “sleep driving” and similar activities that people may engage in under the influence and then not recall (Zammit, 2009).

Zaleplon/Sonata, like zolpidem/Ambien, is also a pyrazolopyrimidine that is structurally dissimilar to benzodiazepines but functions in much the same manner. Interestingly, this class of drugs is being researched for their possible use as nonsedating anxiolytics. Released in 1999 as a hypnotic agent, Zaleplon/Sonata has a very short half-life (about one hour) and induces sleep fairly effectively. A modified release of Zaleplon/Sonata was released in 2011 and seems more useful to treat middle-of-the-night awakening (Greenblatt et al., 2011). Zaleplon/Sonata is a selective agonist at the alpha1-3 subunits of the GABAa1 receptor and like zolpidem/Ambien, was first thought to have low abuse potential (Dooley & Plosker, 2000) but later studies found that to not be true (Paparrigopoulos, Tzavellas, Karaiskos, & Llappas, 2008). At the time of this writing, an aerosol formulation of Zaleplon/Sonata is in development (Avram & Donnelley, 2013).

Eszopiclone/Lunestra is a short-acting hypnotic that belongs to a class of drugs called cyclopyrrolones. Approved by the FDA in 2004, there were nearly 6 million prescriptions written for the drug by 2011 (Greenblatt et al., 2011). The mechanism of action for eszopiclone/Lunestra is still unknown but thought to result from the drugs interaction with GABA receptor complexes located near benzodiazepine receptors (Sonovion Pharmaceuticals, 2012). The results of meta-analyses done to establish the efficacy of nonbenzodiazepines as hypnotics have shown only modest efficacy of eszopiclone/Lunestra in treating insomnia (Huedo-Medina, Kirsch, Middlemas, Klonizakis, & Siriwardena, 2012). There are also adverse effects that can include hallucinations and aggression (Duggal, 2007). Eszopiclone/Lunestra can also cause residual sedation and impair driving ability in the early morning. One of the odder side effects is a bitter, metallic taste in the mouth.

BUSPIRONE: A UNIQUE ANXIOLYTIC

Davis Temple and Michael Eison of Bristol-Myers Company (now Bristol-Myers-Squibb) developed buspirone/BuSpar in 1968. Like so many other psychotropic medications, its development as an anxiolytic was serendipitous. The initial research goal for Temple and Eison was to develop an improved antipsychotic medication. Chemically, buspirone/BuSpar resembles butyrophenone antipsychotics more than anxiolytics. It is classed as an azapirone, a class of drugs that differ in structure and uses in psychiatry (World Health Organization, 2004). Although ineffective in alleviating symptoms of psychosis, buspirone/BuSpar did seem to have antianxiety properties in humans and antiaggression properties in other primates (Schatzberg, Cole, & DeBattista, 1997). In 1986, the FDA approved it for the market, to treat anxiety. Buspirone/BuSpar is classed as an azaspirodecanedione. Buspirone/BuSpar was the first serotonergic drug that showed efficacy for treating anxiety and more specifically GAD (Mokhber, Azarpazhooh, Khajehdalueee, Velayati, & Hopwood, 2010). More recently, buspirone/BuSpar was tried to treat Attention-Deficit Hyperactivity Disorder (ADHD) but methylphenidate/Ritalin was superior to buspirone/BuSpar in treating symptoms of inattention (Davari-Ashtiani et al., 2010). It is also being investigated for efficacy in treating menopausal syndromes (Shumilov & Touitou, 2010).

Although more will be said about buspirone/BuSpar later, we want to address a small detail that students invariably raise in our seminars. We are frequently asked, “Why is BuSpar (the brand name for buspirone) spelled with an upper case “S”? This is a good question for which we had no answer. Finally one of our students (personal communication, Barry Zabielinski, June 1999) tracked down an answer through numerous phone calls to the manufacturer. The manufacturer said there was no esoteric meaning underlying the odd spelling, but the marketing team wanted the brand name to stand out and so capitalized the first and third letters. Another insight into the culture of the pharmaceutical industry!

Mechanisms of Action

As noted, buspirone/BuSpar is unlike the anxiolytic compounds discussed thus far. Although the vast majority exert CNS depression by acting as GABA agonists, buspirone is actually a serotonin agonist and antagonist. Because serotonin is related to certain types of disinhibition of behavior and such disinhibition is also related to relief from anxiety, researchers have hypothesized since the 1980s that serotonin agonists may alleviate anxiety (Feldman, Meyer, & Quenzer, 1997). Buspirone/BuSpar is believed to act as a serotonin antagonist at the 5-HT1a receptors. These receptors are found in parts of the brain associated with fear and anxiety responses including the amygdala, septum, and hippocampus. Readers may be pondering the phrase “serotonin agonist” and wondering if buspirone would be helpful for depression, given that most of the newer antidepressants discussed in Chapter Five are serotonin agonists. Buspirone/BuSpar also acts on the noradrenergic system to increase the firing of neurons in the locus coeruleus. Recall from Chapter Two that such neuronal firing would seem to increase anxiety, not decrease it. How do we account for the fact that in this case the stimulation of these neurons by buspirone/BuSpar is associated with an anxiolytic action? Perry et al. (2006) explain that buspirone’s/Buspar’s effects on the hippocampus and raphe nucleus seem to override this stimulation of the locus coeruleus.

Although not as powerful an agonist of serotonin as a drug such as fluoxetine/Prozac, buspirone has shown some efficacy for treating depression (Julien et al., 2011) but is more often used as a supplement to more conventional antidepressants (Stahl, 2000). Researchers have noted that buspirone/BuSpar may interact with dopamine as a weak agonist in some areas of the brain and as a weak antagonist in others. These effects are not considered clinically significant (Perry et al., 2006). Note that buspirone/BuSpar does not interact with GABA or benzodiazepine receptors, so it does not have significant sedative, muscle relaxant, or anticonvulsive properties.

Side Effects and Dosing

The side effects of buspirone/BuSpar primarily include headache, dizziness, GI upset, and sometimes anxiety and tension. Some patients taking buspirone/Buspar have reported restlessness or fidgeting. Patients suffering from Parkinson’s disease may show a worsening of their Parkinsonian symptoms on buspirone/BuSpar. Buspirone/BuSpar is not recommended during pregnancy or while breastfeeding, mainly because researchers have no data about its effects on fetuses or neonates. Buspirone/BuSpar is not associated with tolerance, dependence, or overdose. Because the drug is not associated with any euphoric or other reinforcing effects, it is not likely to be abused.

Interestingly, buspirone/BuSpar has a more desirable side-effect profile than the benzodiazepines, because it does not impair motor performance to any great degree and does not show any negative interactions with alcohol. Buspirone/BuSpar may exacerbate psychotic symptoms in patients suffering from psychotic disorders because of its weak dopamine agonism. Given this favorable side effect profile, many clinicians have wondered why it is not more routinely prescribed, because it has FDA approval for GAD. Schatzberg et al. (1997) have recommended buspirone/BuSpar as the drug of choice for treating GAD, Social Anxiety Disorder, Mixed Anxiety, and other combinations of depression, and anxiety in patients with a history of substance abuse.

Schatzberg, Cole, and DeBattista point out that many psychiatrists and physicians assume buspirone/BuSpar is weaker and slower to work than benzodiazepines, particularly in patients who have a history of being treated with benzodiazepines. These authors note that if patients like the more immediate effects of sedation that follow the first dose of benzodiazepines, they may think buspirone/BuSpar is not working, because it lacks this effect. Both benzodiazepines and buspirone/BuSpar take two to four weeks before reaching maximum therapeutic effects, although the patient feels the impact of benzodiazepines within an hour of the first dose. Schatzberg and colleagues did not note that until going generic, buspirone/BuSpar was one of the most expensive anxiolytics on the market (Modell, 1995), which may have accounted for its less frequent use by prescribing professionals. Benzodiazepines can be problematic in that their withdrawal effects may be similar to (or worse than) the anxiety symptoms clients initially began taking them to dispel. Buspirone/BuSpar has little to no tolerance or withdrawal effects and therefore is a more flexible drug to use with such clients (Chodera, Nowakowska, & Bartczak, 1994).

Because buspirone/BuSpar does not interact with GABA receptors at all, it has some advantages over benzodiazepines. These are summarized in 

Table 6.5

.

As Schatzberg et al. (1997) noted, though, buspirone/BuSpar does not give the immediate effect of drowsiness that is typically anxiolytic. Many people with anxiety who have taken benzodiazepines may mistake the lack of this effect for evidence that the buspirone/BuSpar is not working. Clients need to be informed that buspirone does work differently from benzodiazepines and should be told not to expect the same sensations when taking buspirone/BuSpar.

TABLE 6.5 Advantages of Buspirone Over Benzodiazepines

Lacks hypnotic, anticonvulsant, and muscle relaxant properties

Much less likely to induce drowsiness and fatigue

Does not impair psychomotor or cognitive function

Shows little potential for abuse and dependence

Does not induce tolerance

Has no synergistic effect with alcohol

Lacks affinity for GABA and benzodiazepine receptors

Is not cross-tolerant with benzodiazepines

© Cengage Learning®

Although dosing is done by the prescribing professional, mental health clinicians should be aware some psychiatrists think that many clients go off buspirone/BuSpar because they do not believe it is working and that this in turn is related to not having a high-enough initial dose. Perry et al. (2006) advise that the usual dosage for anxiety is between 15 and 45 mg per day, given b.i.d or t.i.d. (from the Latin bis in die, “twice a day”; ter in die, “three times a day”), but this can be increased to as high as 60 mg per day.

Tolerance, Dependence, and Overdose

As noted in Table 6.5, some of the strongest arguments in favor of using buspirone/BuSpar are that it does not induce tolerance and dependence. In addition, it is highly unlikely that clients could overdose on buspirone. These effects seem minimal to nonexistent with buspirone, primarily because of its mechanisms of action, which are wholly different from those of benzodiazepines. A note of caution should be added, though. Recall from Chapter Five that serotonergic antidepressants were once believed to not induce tolerance and dependence and that this has since been disproved (Schatzberg, 1997). Therefore, prescribers may do well to watch for a discontinuation syndrome in longer-term users of buspirone at higher doses.

Before discussing a case, let’s summarize when buspirone/BuSpar may be better for a client than a benzodiazepine. Benzodiazepines are effective when used over short periods or infrequently (p.r.n.). Clients with fairly severe anxiety on a chronic basis are good candidates for trying buspirone/BuSpar. A review of studies indicated that buspirone/BuSpar may be helpful in clients with GAD. There are mixed results for buspirone’s/BuSpar’s effectiveness in other disorders (Perry et al., 2006). Thus clients would likely be taking something every day to treat their anxiety, so buspirone/BuSpar is attractive in that it has not been shown to induce tolerance or dependence. Generally speaking, many clinicians believe buspirone/BuSpar is worth trying with anxious patients who have a history of abusing alcohol or benzodiazepines. Because alcohol is something adults have access to, these clients may drink but the alcohol does not interact negatively with the buspirone. Finally, Stahl (2000) wrote that buspirone/BuSpar may help older clients with anxiety because it is well tolerated and does not seem to have significant pharmacokinetic drug interactions.

The Case of Meredith

Meredith, a 38-year-old married defense attorney, has suffered from extreme anxiety for most of her life. She has a very strong aversion to psychotherapy and believes there should be a pill to cure her worries. Over the years, she has expressed a dislike for the benzodiazepines (she tried several) because they often induced drowsiness and fatigue. She also tried an SSRI, which made her more agitated after two weeks.

At her next appointment, her primary care physician suggested buspirone/BuSpar, a drug that for some reason Meredith had not known about. She began a course of buspirone/BuSpar 15 mg b.i.d. for her anxiety. After about six weeks Meredith noted a decrease in her daily levels of anxiety and reactions to stress. She also felt herself gain some perspective on the professional and personal issues that she often avoided. She recognized that the buspirone/BuSpar did not impair her level of functioning at work, and in fact she found she was more effective now that her anxiety had diminished. She also appreciated that the side-effect profile of buspirone/BuSpar was better than that of the benzodiazepines.

Meredith took the buspirone/BuSpar for over 18 months and then recognized a need for psychotherapy to address conflicts and issues not resolved by the medication, exercise, or stress reduction techniques that she incorporated into her life. In the treatment, Meredith focused on her sense of isolation and unhappiness in her marriage, her surfacing sexual feelings toward women, and the pain from her childhood because her family moved 10 times to different cities. Once in therapy, after seven months Meredith stopped taking the buspirone/BuSpar. Meredith is one of many who discovered buspirone/BuSpar as an effective anxiolytic.

Review Questions

• How are nonbenzodiazepines similar to and dissimilar from benzodiazepines?

• Why is buspirone a good medication for people recovering from drug or alcohol use problems?

SECTION FIVE: NEWER APPROACHES TO ANXIOLYTIC MEDICATIONS

Learning Objectives

• Be able to discuss two new approaches to anxiolytic medications.

• Know the DSM-5 changes to Anxiety Disorders.

In the first edition of this book, we discussed propranolol/Inderal (a beta-blocker) and clonidine/Catapres (a hypertension medication) as potential anxiolytics. Since then there have been no studies showing strong statistical significance for those agents in treating anxiety. Interestingly, as many states are decriminalizing marijuana, cannabis, some of the psychoactive elements in cannabis are being explored for anxiolytic properties. Cannabidiol (CBD) is one of 60 active cannabinoids found in cannabis sativa. In animal models, it produces significant anxiolytic properties (Almeida et al., 2013; ElBatsh, Assareh, Marsden, & Kendall, 2012). It has also been found to be useful in reducing anxiety in healthy volunteers suggesting that future trials with people who suffer from Anxiety Disorders are warranted (de Mello Schier et al., 2012). As the United States rethinks its drug laws and drug schedules, it may be that decriminalization brings to the market effective and affordable anxiolytics either through decriminalizing cannabis or designing medications from the active elements of cannabis. In addition to cannabis compounds, we will discuss kava and melatonin as anxiolytics in the chapter on herbaceuticals.

Other newer approaches to anxiolytics include focusing on the corticotropin releasing factor type 1 (CRF1) receptor. The peptide CRF plays an important role in the proper functioning of the stress response system through its action on CRF1 receptors. The hypothesis here is that in anxiety disorders in people with early life trauma, the trauma may have affected the CRF1 receptors via epigenetics. In these cases, it seems in animal models that blocking the CRF1 receptor brings about anxiolysis (Kehne, 2007). Another agent, Etifoxine/Stresam, has been around since the 1960s and seems to exert an anxiolytic effect as a translocator protein that enhances neurosteroidogenesis and as a weak direct GABAa receptor enhancer. The drug, which is also used for axonal regeneration, has been shown to block panic in rodents (Nothdurfter et al., 2011) and shows promise for treating PTSD (Pinna, 2014).

We would be neglectful if we did not add that psychotherapy has been shown to be very effective in the treatment of DSM-5 Anxiety Disorders (remember these no longer include OCD or PTSD). In a recent meta-analysis, Cuijpers et al. (2013) found that there was no statistical difference between the efficacy of psychotherapy and pharmacotherapy for 27 studies focusing on Anxiety Disorders. This included studies where anxiety was being treated with antidepressant medication and studies where the anxiety was being treated with anxiolytic medications. Even when medication is combined with psychotherapy we tell clients that the medication provides a “chemical window of opportunity” during which it may be easier for the client to begin therapy but which is not necessary to carry on with for years.

The Case of Starr

Starr, a local 18-year-old high school track and field star living in Colorado, began to get very nervous during track season and this worsened before each track meet. Her symptoms were increased heart rate, sweaty palms and feet, and palpitations. As a result of these symptoms, she experienced a loss of concentration and confidence. She discussed this mounting problem with her coach, who suggested she talk to her family physician. The physician prescribed a low dose of buspirone/BuSpar. Starr reported that the medication made her feel tired and sometimes even more nervous. At about this time, Starr experimented with eating cookies with cannabis in them. As a result, she experienced an anxiolytic effect that she said made her feel “normal” again. She continued to use cannabis (eating it in baked goods) on the weekend and as her track team did not have a drug testing requirement her use was never detected. She claims that the anxiolytic effects lasted well into the week. Although Colorado decriminalized cannabis for recreational use she is still underage for legal use of the substance and is hiding this from her parents who think she is still taking buspirone. In Starr’s case how would you weight the risks and benefits of what she is doing?

Review Questions

• How might cannabinoids be used to develop anxiolytic medications?

• How would you describe the changes to the Anxiety Disorders in DSM-5?

SECTION SIX: SSRI TREATMENT OF ANXIETY

Learning Objectives

• Have a general idea of what the anxiolytic mechanism is for SSRI antidepressants when they reduce anxiety.

• Understand that clients will have a heterogeneous response to SSRIs and it is hard to predict client to client who will benefit from them.

Clinicians have long known that antidepressants also reduce anxiety in clients taking them. Recall from Chapter Five that anxiety and depression are often comorbid; in fact, several opponents of categorical psychiatry feel anxiety and depression may form two ends of a symptom continuum. Researchers as early as Klein (1967) have noted the impact of antidepressants on symptoms of anxiety. Although most antidepressants seem to have some value in treating anxiety (Rickels & Rynn, 2002), some of the more chemically atypical agents such as bupropion do not, and actually may exacerbate anxiety. Clinicians must also allow for the possibility of an unpredicted, idiosyncratic response. Because, as we have pointed out, depression and anxiety are probably overdetermined disorders, it is not possible to state with certainty what the impact of taking any particular medication will be.

Serotonin appears to be implicated in anxiety either through the serotonin transporter (SERT) or the 5-HT1a receptor. The serotonin transporter-linked polymorphic region has two variations; one short and one long (Lee et al., 2005). People with the short form who experience stressful life events are more likely to develop psychological symptoms (Celada, Bortolozzi, & Artigas, 2013). In studies where mice are bred without 5-HT1a receptors, these mice show more susceptibility to anxiety in anxiogenic situations and because all neurotransmitter systems in the brain influence one another, knocking out 5-HT1a receptors in these mice also seems to alter GABA functioning (Celada et al., 2013).

The Case of Katrina

Katrina, a 57-year-old widow who worked as a secretary for a local grocery distributor, developed immobilizing anxiety symptoms about four years after her husband’s death. In fact, over time she was diagnosed with Generalized Anxiety Disorder, Panic Disorder with Agoraphobia, and Persistent Depressive Disorder (previously Dysthymia in DSM-IV ). Katrina staunchly opposed taking any form of medication, even aspirin or vitamins, but she did believe in talk therapy. She said, “I have heard many people on television and radio speak to the benefits that they received from psychotherapy.” In fact, after her husband’s death Katrina was helped a great deal by a female therapist at the local mental health center. The therapy was supportive and insight-oriented and lasted six months on a weekly basis, with two follow-up sessions.

Katrina had sought help from a cognitive-behavioral male therapist, a feminist therapist, a support group for people suffering with anxiety and phobias, a hypnotherapist, and now a psycho-analytically oriented psychotherapist. None of the approaches appeared helpful in reducing Katrina’s symptoms. Four of the five therapists recommended she have a psychiatric evaluation. Katrina refused all recommendations.

In her work with the dynamic therapist, Katrina gradually discovered aspects of her resistance to any changes and great distrust in both modern medicine and medications. Her therapist diligently explored these issues with her and began to teach her about more recent psychopharmacologic developments related to anxiety disorders. Katrina became slightly more open to discuss the possibility of a psychiatric assessment, and she expressed interest in the SSRIs. Eventually Katrina saw a psychiatrist who prescribed paroxetine/Paxil, and she reluctantly agreed to it. After eight weeks, Katrina noticed a lessening of her fears and anxiety. Her panic all but disappeared. She did have several life issues that she continued to address with her therapist, but the SSRI treatment greatly reduced her symptoms of anxiety.

In Katrina’s case, by addressing her intrapsychic issues her therapist was able to maximize therapeutic impact by combining a medical model intervention with an intrapsychic intervention. Katrina improved, and 16 months later titrated off the paroxetine/Paxil. We summarize the efficacy of antidepressants later, while discussing pharmacologic interventions by disorder.

The Case of Nicole

Nicole, a 35-year-old single woman, sought, from her psychiatrist, relief for a long-standing depression with features of anxiety. At the time of referral, Nicole was experiencing great difficulty sleeping, constant worry, mild panic, and a constant depressive affect (mood). Her physician prescribed paroxetine/Paxil at 10 mg and told her to increase to 20 mg at the end of the first week. Nicole noticed during the first week that she was more agitated and slept even less. Because her doctor had not warned her about these possible side effects, she increased the dosage at the end of the week to 20 mg. By the second day after the increase, Nicole was experiencing total panic and terror. At times she could not breathe, and in her hypervigilant state she could barely speak to her neighbor, who wisely called the EMT service. Nicole was taken to the emergency room at the local hospital, where she was prescribed a mild tranquilizer. The attending physician called her psychiatrist, and they agreed that Nicole was experiencing an SSRI-induced panic attack and she was taken off the paroxetine/Paxil. When Nicole recovered from her panic attack, her psychiatrist prescribed alprazolam/Xanax p.r.n. and encouraged her to seek therapy. He also indicated that if she still felt depressed in about two weeks, he would try a different class of antidepressant.

The Case of Rhonda

Rhonda was a 38-year-old divorced mother who had been in weekly therapy about a year. Near the end of the first year of her work, Rhonda became very depressed and requested a psychiatric consult. The psychiatrist recommended sertraline/Zoloft, a new SSRI that had just received FDA approval. Rhonda began the sertraline/Zoloft at 100 mg and soon was taking 200 mg per day. She reported feeling better but noticed she was losing large amounts of her beautiful hair daily, which she linked directly to the sertraline/Zoloft. Her therapist recommended she talk to the psychiatrist, who checked the side effects and found nothing about hair loss. However, she decreased the sertraline/Zoloft for Rhonda to 100 mg daily and the hair loss ceased.

I (Rak) also noticed this hair loss in two other female clients who took sertraline/Zoloft at 200 mg. I reported this to a middle manager at Pfizer, who indicated he would look into the situation, but I never received a further response. Sertraline/Zoloft now is seldom prescribed at 200 mg per day.

Review Questions

• What is the therapeutic mechanism of action of SSRI antidepressants when they work for anxiety?

• What would you tell a client who was starting an SSRI medication regimen hoping to alleviate anxiety?

SECTION SEVEN: ANXIOLYTIC THERAPY BY DIAGNOSIS

Learning Objective

• Know the general treatment approaches for each diagnosis.

As stated earlier, in this section we summarize recommended therapies for anxiety symptoms by diagnosis. We summarize the pharmacologic interventions and also touch on the psychological interventions. As we have stated from the beginning, an integrative view of the topic demands that these interventions be held in mind so that the reader does not unwittingly become mesmerized by the word magic of pharmacologic interventions. We cover GAD, Panic Disorder, Agoraphobia, and Social Anxiety Disorder and Specific Phobia. Even though PTSD is no longer considered an Anxiety Disorder proper (it has its own category in DSM-5), we will touch on anxiolytic treatment of that disorder.

Generalized Anxiety Disorder

GAD is considered the basic anxiety disorder, because it is characterized by intense, unfocused anxiety. DSM criteria for this classification require excessive anxiety and apprehensive expectation more often than not for at least six months before the diagnosis is made. Adults must manifest three of the symptoms in the symptom list; children, only one. In children this used to be called Overanxious Disorder of Childhood and has a high comorbidity with ADHD and Major Depressive Disorder as well as other anxiety disorders. The focus of the intense anxiety varies developmentally. Adults tend to worry about minor daily life events, whereas children tend to worry about athletic, academic, or social competence. It is crucial that clinicians explore the worry of children and adults for other emotions such as sadness, loss, rage, and other symptoms that reflect the aspects of “worry.” People with GAD are vigilant regarding potential threats in the environment but do not have particular images of threats. These people actually show less physiological responsiveness (heart rate, blood pressure, respiration) to anxiety-provoking stimuli than do people with other anxiety disorders. For this reason people with this disorder have been called “autonomic restrictors.” This may be explained as follows.

Recall that the autonomic nervous system regulates involuntary sympathetic and parasympathetic functions. Autonomic restriction has been linked to intense thought processes or worry that never develops to specific, consistent images of potential problems. The images would elicit more negative emotions. Their style keeps such autonomic restrictors from feeling these potentially negative emotions but also from working through their anxiety in therapy (Barlow & Durand, 2002).

Pharmacological Treatments for GAD

GAD is considered a challenging disorder to treat. Although benzodiazepines have been a staple of treatment until recently, they do not alleviate all symptoms and are significantly correlated with increased costs due to things like falls and accidents while under the influence of the drugs (particularly in elderly clients) (Berger, Edelsberg, Treglia, Alvir, & Oster, 2012). Also, benzodiazepines carry the risk of tolerance and dependence whereas drugs like SSRIs and buspirone do not and have similar efficacy (Bandelow et al., 2013; Mokhber et al., 2010). Although most benzodiazepine users do not abuse their medication, some question whether it is worth the risk to use them long-term (Baldwin, 2012). Many researchers (such as Schatzberg, Cole, & DeBattista, 2010) thus believe buspirone is the ideal medication of first choice for GAD. As noted, Bandelow and colleagues (2013) found that buspirone/BuSpar compared favorably with the benzodiazepines. Unlike benzodiazepines, buspirone/BuSpar cannot be used on a p.r.n. basis. Like the SSRI antidepressants, it seems to require daily dosing to exert its effects. Buspirone/BuSpar may also take two to four weeks for the full therapeutic benefit to be achieved. Recent research on the SNRI antidepressants (e.g., Effexor/venlafaxine; Prestiq/desvenlafaxine) are as useful for GAD as SSRIs and buspirone/BuSpar. One persisting problem is that many clients discontinue treatment with SSRIs and SNRIs because of the side-effect profile and many state a preference for benzodiazepines (

Table 6.6

). There are a great number of unmet needs in the population of people suffering GAD and hopefully some of the newer anxiolytics in development will provide relief with fewer side effects (Chollet, Saragoussi, Clay, & Francois, 2013).

Psychological Treatments for GAD

Regardless of the pharmacotherapy used when treating GAD, it is important to combine medication with some form of counseling or psychotherapy. The long-term nature of the condition and the lack of long-term efficacy studies both support supplementing medication with a psychosocial intervention. In reviewing the treatment literature, Bandelow et al. (2013) found that variations of cognitive-behavioral therapy (CBT) consistently show superiority over no treatment at all. These authors also note that the dropout rates in psychosocial treatment trials have been low and that the combination of CBT with progressive relaxation and/or exposure seems to have the best possibility of long-lasting change.

TABLE 6.6 Psychotropic Medications That Combine With SSRIs to Treat OCD

SSRI and Buspirone

SSRI and Trazodone

SSRI and Lithium

SSRI and Benzodiazepine

SSRI and Zolpidem

SSRI and typical antipsychotic

SSRI and atypical antipsychotic

© Cengage Learning®

This recommendation is not intended to rule out other types of therapy such as psychodynamic therapy but, as is often the case, there are more studies of CBT and behavior therapy, partly because they are easier to study with operationalized variables. Psycho-dynamic therapy for GAD aims to help clients gain awareness of unconscious conflicts and underlying anxiety-provoking drives, recognize the environmental cues that activate anxiety, and understand the origins of anxiety in early life experience. Three questions typically underlie this treatment:

1. What inner drive is the client afraid of?

2. What consequences of overt behavioral expression of the drive does the client fear?

3. What psychological and behavioral measures does the client take to control the drive?

In seeking to answer these three questions, the clinician also confronts various perplexing symptoms expressed by the client, and defense mechanisms that initially hinder the therapy. Clients considered good candidates for insight-oriented therapy are those willing to engage in (and capable of) introspection and to reflect on that introspection, those who can tolerate the expression of painful psychological material, and those who can form meaningful relationships. It is important that these clients be motivated to aim for psychological change and growth as opposed to just symptom relief.

Panic Disorder

As noted earlier, in DSM-5 and ICD-10 (and the forthcoming ICD-11) Panic Disorder is uncoupled from Agoraphobia. Panic Disorder is typically treated in two phases. The first is aimed at reducing the frequency and/or intensity of the panic attacks. This phase is frequently accomplished pharmacologically. The second phase involves administering the psychosocial treatment in the hope of decreasing the dysfunctional responses that become panic attacks (American Psychiatric Association, 2000a). Interestingly, numerous drugs that affect different parts of the central nervous system all seem effective in reducing panic attacks (Speigel, Wiegel, Baker, & Greene, 2000). For the first phase of treatment, high-potency benzodiazepines are very effective, work quickly, and reduce anticipatory anxiety. Over 60 trials on benzodiazepines have been made on subjects with Panic Disorder, and the data suggest that these clients continue to improve up to six months, at which point gains stabilize. These medications can be prescribed p.r.n., so clients need only take the dose when they feel in imminent danger of a panic attack. Obviously, the more frequently clients use any benzodiazepine, the more likely the problem of tolerance and dependence.

Numerous trials have been conducted to assess the efficacy of antidepressants for the treatment of Panic Disorder. Summarizing literature across 15 years, Perry et al. (2006) noted that approximately 67% of subjects could be said to respond to treatment with tricyclic antidepressants and MAO inhibitors. “Response” was defined as anywhere from an 80% reduction in panic attacks to complete remission. SSRI medications generally showed a 60% response rate, where response was defined as a decrease in panic severity. Several SSRI compounds have on-label FDA approval for treatment of Panic Disorder, including sertraline/Zoloft and paroxetine/Paxil.

Several psychosocial interventions are highly successful for the second phase of Panic Disorder treatment, and from an integrative perspective we would be remiss if we omitted mention of these. Traditionally, treatment centered on gradual exposure to feared situations (in cases where agoraphobia was a component) and anxiety-coping mechanisms such as relaxation. A recent study estimated costs associated with the treatment of Panic Disorder. Costs included the cost of the treatment as well as indirect costs like lost productivity. Cognitive behavior therapy had lower overall costs associated with it than cognitive therapy plus SSRIs and SSRIs alone (van Apeldoorn et al., 2014). With the changes in how we approach health care in the United States especially, studies like this are important to sort out what is going to do the most good and provide the best value.

Social Anxiety Disorder and Specific Phobias

Because DSM-5 has just this year (at time of this writing) uncoupled Agoraphobia from Panic Disorder, we have no treatment guidelines proper for Agoraphobia. For our purposes, think of it as similar to the approaches we will discuss for treating Social Anxiety Disorder and Specific Phobias. Although Social Anxiety Disorder (previously Social Phobia in DSM-IV) and Specific Phobias may vary in the focus of the fear, they share several similarities that allow us to group them together in this section. They both seem to be an outgrowth of an evolutionary mechanism that prepared humans to flee dangerous situations, and they are both problematic in that the flight response is out of proportion to the actual danger posed by the situation. In the past few decades, we have seen a rise in studies on the physiological underpinnings of these disorders including genes, neurotransmitters, the hypothalamic-pituitary-adrenal (HPA) axis, and epigenetic triggers in the environment (Dalrymple, 2012; Gimenez et al., 2014; Lueken et al., 2013). It should also be noted that some (Dalrymple, 2012) wonder if Avoidant Personality Disorder is not really the same disorder or perhaps two disorders on the same spectrum. Again, these are all disorders for which several effective psychological interventions are available and we will touch on those briefly.

Social Anxiety Disorder

Having a Social Anxiety Disorder (SAD) is being extremely and painfully shy. Just as it can be hard to differentiate SAD from Avoidant Personality Disorder, it can be hard to differentiate SAD from shyness as well. It manifests as a marked or persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or possible scrutiny. The main fear is that the person fears acting in a way that will be humiliating or embarrassing to him- or herself. Although social anxiety disorder treatments are newer, group therapy involving role-play and rehearsal of the feared situation both seem effective (Turk, Heimberg, & Hope, 2001). As with specific phobias, exposure to the anxiety-provoking situation is an important part of the treatment. Also as with specific phobias cognitive behavioral treatments are very efficacious in treating SAD (Schreiber, Heimlich, Schweitzer, & Stangier, 2013; Willutzki, Teismann, & Schulte, 2012). There have also been studies supporting a newer variation of cognitive therapy called mindfulness-cognitive behavior therapy in treating anxiety disorders (Kim et al., 2013).

Given that psychological treatments are so effective, what is the rationale for prescribing medications? Again, the answer is that often the medications can give clients a window of opportunity (of relief from symptoms) that then allows them to confront their issues in counseling and make the necessary changes. This is particularly important for clients who are so limited by their symptoms that they cannot fulfill important obligations. Research studies support that pharmacotherapy is effective in reducing the severity of symptoms in the short term but cognitive therapies are more effective reducing symptoms and changing avoidance behaviors in the long term (Dalrymple, 2012). SAD in particular has received a great deal of attention over the past five years from the makers of SSRI medications. Several SSRI medications have received FDA approval for treating SAD, including Paxil/paroxetine and Zoloft/sertraline. SNRI agents like Effexor/venlafaxine are also used to treat SAD. Two-thirds also respond to MAO inhibitors and the tricyclic clomipramine/Anafranil but, as noted in Chapter Five, the SSRI side effects are less difficult to manage than those from MAO inhibitors or TCAs.

Review Question

• What are the first-line choices of medication for Generalized Anxiety Disorder, Panic Disorder, Social Anxiety Disorder and Specific Phobia?

SECTION EIGHT: FOCUS ON PSYCHOLOGICAL, CULTURAL, AND SOCIAL ISSUES

Learning Objectives

• Think about the extent to which culture and the pace of Western societies contributes to anxiety.

• Consider how popular media could be used more effectively to educate lay people about what counseling and psychotherapy can offer.

PSYCHOLOGICAL ISSUES

Anxiety Disorders: Myth or Reality

The debate about the nature and source of anxiety continues. Is anxiety a product of an overwhelming state of tension (Barlow & Durand, 2002), a sign of psychological conflict (Freud, 1925), or both (Gabbard, 1994)? If we examine anxiety from a psychological perspective it is possible to arrive at one point of agreement: Clinicians who treat clients suffering from anxiety disorders understand that these clients have cognitive, affective, and interpersonal struggles that are entwined in their anxiety symptoms. No medication is going to address all of these struggles, which is where psychotherapy enters the picture. In every case we reviewed and shared here, counseling played a crucial role in the client’s recovery. When talking with clients, we find that psychological issues range from anxiety resulting from situational stress to severe PTSD. Each disorder potentially encompasses underlying issues and conflicts that cannot be ameliorated by medication alone.

I (Rak, the second author of this book) have trained to become a psychoanalyst. This training involved four to five days a week treatment focused on psychological conflicts and is designed to prepare one to be a psychodynamic therapist. (A psychoanalyst provides four- to five-day-a-week treatment focused on the psychological conflicts of the patient who usually lies on a couch. Intensive psychotherapy is one- or two-day-a-week counseling that is eclectic in nature, and psychodynamic psychotherapy is counseling or therapy that is guided by psychoanalytic principles, but is not an analysis.) My view of profound anxiety resonates with that of some clinicians in the field. I believe serious anxiety can be understood only in the context of the transference in intensive psychotherapy where counselor and client search beyond the symptoms for underlying beliefs, feelings, and attitudes, conscious or unconscious. These conflicts and wishes repeatedly trigger the client’s anxiety and must be integrated into the client’s concept of self before any long-lasting relief can be accomplished. Taking a broader perspective, Barber and Luborsky (1991) have argued that specific anxiety disorders required varied treatments with different clients. Psychodynamic psychotherapy may be the treatment of choice for those clients who are psychology minded and willing to invest the time to explore their anxiety. Clients who want more direction from their mental health clinician may do better with a cognitive behavioral approach. Other clients whose anxiety is directly tied to a felt need to make difficult but necessary choices (such as whether to keep a safe but boring job or risk an exciting but less secure job) will likely benefit from an existential approach to therapy. As we have discussed throughout the chapter, anxiolytics have a range of effectiveness with symptoms of anxiety disorders, but they may or may not be the total solution for the client’s problem. Understanding the intrapsychic elements of each client’s anxiety guides us in selecting an appropriate counseling intervention to complement whatever medication regimen they may be on.

Gabbard (1994) concluded that the treatment of anxiety disorders must begin with careful and thorough psychodynamic evaluation. In making this evaluation the therapist should be aware that the symptoms may only be the proverbial “tip of the iceberg” for the client. The mental health professional needs to assess the nature of the client’s underlying fears, capacity to tolerate treatment that explores those fears, worry that the anxiety is destroying the self, and the client’s relationship with important others or lack thereof. After an assessment and evaluation, the professional considers the range of treatments for anxiety, including brief therapies, cognitive-behavioral therapy, existential and humanistic therapies, psychodynamic theory, psychoanalysis, and long-term expressive-supportive psychotherapy. In cases such as those presented in this chapter, the professional must consider which approach may be most helpful to each client.

More recently a unified protocol for the transdiagnostic psychodynamic treatment of anxiety disorders was developed that draws from empirically supported treatment principles. These principles are: (1) socializing the client for therapy, (2) motivating the client and setting goals, (3) establishing the helping alliance (relationship), (4) identifying a core conflict thought to underlie the anxiety, (5) focusing on the warding-off, wish/affect, (6) modifying internalized object relations, (7) understanding and modifying defenses and avoidance, (8) modifying sense of self, and (9) ending therapy and setting up relapse prevention (Leichsenring & Slazer, 2013). In addition, short-term psychodynamic therapies have been shown to be effective for anxiety disorders (Bressi, Procellana, Marinaccio, Nocito, & Magri, 2010).

We believe the complex issues that arise in clients contribute to the complexity and mystery of anxiety disorders. Some clients maintain their high levels of anxiety in order to live out their lives in a compromised fashion. In one example provided earlier, I (Ingersoll) worked with a client who chose not to pursue the exciting job opportunities and stay in the safe but boring job. Although his anxiety decreased significantly after making his choice, he was then beset by bouts of depression. From an existential perspective the client had traded freedom for comfort and this was signaled by the depression. He re-entered treatment five years later when another opportunity to take a more exciting but less secure job presented itself and his anxiety reappeared. Some clients can find relief only from supportive counseling, whereas others require compulsive behaviors to distract them from their suffering. This strategy of seeking relief through distraction is one of the prominent motivations driving the consumer culture in the United States. From an existential perspective, the consumer culture provides distractions from the anxiety that comes when one is aware of the freedom one has and the consequences of trading it for security. For the client with the job dilemma, his current (but boring) job paid well and he was able to afford expensive pleasures (like vacations), but the relief these pleasures provided was temporary. It is most beneficial to clients not to oversell medications as a definitive treatment, but to help them understand that anxiety is an important sign of issues to explore in counseling or psychotherapy.

Cultural Issues

The pressures of American culture in general are enormous external contributors to anxiety especially in the post-9/11 era. The continued struggle for civil rights for all Americans, psychological responses to war, the horror of the terrorist attacks, the corruption of many working the stock market, an increasing mistrust of government, the increased turmoil and violence of our youth, and the dismantling and or transformation of traditional values all trigger anxiety reactions. Our culture is infused with paradigms of violence, revenge, conquest, and dominance. The influence of culture is a powerful variable in understanding the rise of anxiety disorders. The impact of these external stressors varies with the psychological makeup of each client.

The American tendency, particularly in the consumer culture and mass media, to glorify violence continues to make major contributions to stress and anxiety in Americans, although evolutionary dynamics related to reproduction can always account for a certain percentage of violence (fighting for the best mate to reproduce with) (Wright, 1994). Violence is also reinforced by unrealistic portrayals in almost all mass media (Bushman & Anderson, 2001). The question remaining is the extent to which this contributes to anxiety, but it is certainly a useful working hypothesis in that being the target of or viewing aggression increases anxiety.

Tseng (2001) further elaborated on the external cultural pressures of anxiety by exploring its cross-cultural dimensions. He addressed the issues of how different cultures reveal their emotions. Some do so with gestures and facial expressions, others with words, still others through the body. Some cultures have highly elaborate cultural ways of expressing emotions through “somato organ language,” incorporating into the language words or terms that represent somatic pain without a complete awareness of its psychological origins for affective expressions. For instance, fa pi qi (“lost spleen spirit,” meaning losing one’s temper) and gan fuo da (“elevated liver fire,” meaning emotionally irritated) in Chinese are equivalent to organ language expressions used in English, such as “butterflies in stomach” or “a pain in the neck” (p. 292).

Tseng further elaborated that it is difficult for patients to present a clear picture of their distress if they are from a culture where the condition is viewed as a holistic experience rather than as a series of specific symptoms from the descriptive psychiatry perspective. Tseng further discussed specific culture-related syndromes such as Dhat syndrome in India (fear that excessive semen loss will result in illness) and Malignant Anxiety syndrome in Africa (intense feelings of fear and anger from extreme cultural disruption that lead to homicidal feelings). From the cultural perspective, it is clear that anxiety disorders are subject to a variety of cultural influences and the cultural “language of expression” of the client. Therapists need to be alert to these both subtle and overt manifestations of anxiety from clients. Most therapists in practice today, especially in urban settings, encounter increased numbers of clients from diverse cultural backgrounds.

Social Issues

From the perspective of third-party payers (managed care), the most appropriate treatment for a client (counseling) may be cost-effective but is not always valued in Western culture. In the United States, pharmaceutical companies have two lobbyists for every member of senate and congress. This is an enormous amount of lobbying power that drives legislators to favor giving money via Medicaid and Medicare to pharmaceutical interventions rather than talk therapy interventions. Think of it this way: when was the last time you saw a commercial for counseling? This further deepens the dilemma we have noted so often throughout the book: that psychotropic drugs alleviate many symptoms of anxiety disorders, even though we do not fully understand the pharmacokinetics and the pharmacodynamics of the drugs, yet they do not necessarily lead to deep and maintained gains for all clients. The pressures from managed care to treat most, if not all, anxiety disorders with psychotropics and brief models of counseling are enormous. It is crucial that we become and remain alert to clients whom these strategies do not help.

As detailed in other chapters, the role and influence of the pharmaceutical companies cannot be overlooked in treating anxiety disorders. The surge in the uses of SSRIs for anxiety conditions indicates the drive of these companies to influence the psychiatric treatment market with an arsenal of psychotropics. This occurs in the context of growing confusion, as discussed in earlier chapters, about distinctions between anxiety and depressive disorders and about their comorbidity.