Chapter 5: The Antidepressant Era PDF

C H A P T E R F I V E The Antidepressant Era The title of this chapter derives from a book of the like ketamine. Section Seven covers important psy- same title by David Healy (1997). Healy...

C H A P T E R F I V E The Antidepressant Era The title of this chapter derives from a book of the like ketamine. Section Seven covers important psy- same title by David Healy (1997). Healy points out chological, cultural, and social perspectives on anti- the important but overlooked fact that depression depressants including the concerns about violent proper (what the DSM-5 calls Major Depressive behavior being correlated with antidepressant Disorder) [American Psychiatric Association therapy. (APA), 2013] was basically unheard of as recently as 50 years ago. For Healy, the antidepressant era unfolded against a backdrop of battles within the SECTION ONE: THE CURRENT IMPACT psychiatric profession (people endorsing the medi- OF ANTIDEPRESSANTS cal model perspective battling those endorsing models emphasizing a psychological perspective), regulatory agencies such as the Food and Drug Learning Objectives Administration (FDA), and the pharmaceutical Know what the point and lifetime prevalence of Major industry. Antidepressant medications are among Depressive Disorder is. the medications most advertised directly to consu- Understand the conditions that are often comorbid mers and evidence is mounting that this does not in with depression. fact increase consumer knowledge about depression Be able to articulate sex differences in reported rates and antidepressants but rather increases mispercep- of depression. tions like the discredited chemical imbalance theory Know what meta-analytic studies note as the overall of depression (Park, 2013). efficacy of antidepressants. This chapter is divided into seven sections. Section One provides an overview of the current impact of antidepressants and Major Depressive Disorder. A television commercial features a grimacing young Section Two describes early theories of antidepres- man with his face against a wall. The commercial’s sant action. Section Three covers the neurotrophic/ narrator lists several symptoms of fear and anxiety plasticity theory of antidepressant action and other related to Social Anxiety Disorder (previously newer findings. Section Four begins coverage of Social Phobia in DSM-IV ). The last scene in the the classes of antidepressant medications with what commercial shows the same young man smiling, are called first generation antidepressants. Section rising from a table in a crowded room apparently Five is devoted to selective serotonin reuptake inhi- to receive acclaim for some accomplishment. The bitors (second generation antidepressants). Section ad ends by repeating the name of the medication Six covers third-generation antidepressants like and informing the viewer, “Your life is waiting.” As bupriopion and duloxetine and experimental drugs we noted in Chapter Four, there is vigorous debate 82 Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 83 as to whether such ads are a valuable source of antidepressants examine their use in treating Major information or prey on the misconceptions many Depressive Disorder as defined by DSM-5. Thus, people have about such drugs being “magic before discussing the history of antidepressants, potions” to change their lives. let’s review Major Depressive Disorder proper. At this writing, antidepressants are still one of the most advertised and prescribed psychotropic medications. Over $11 billion is spent annually for antidepressants and it is estimated that between MAJOR DEPRESSIVE DISORDER (MDD) 17 million (Ross, 2012) and 22 million Americans The 12-month prevalence of MDD is approxi- (IMS Health, 2014) take them. In the late-20th mately 7% with significant differences across age century prescriptions for antidepressants for chil- groups. For example, the prevalence in 18–29 dren increased at an exponential rate (Bostic, year olds is three times higher than in people 60 Wilens, Spencer, & Biederman, 1997) despite years or older. It seems that male children are scant evidence to support their use for children more prone to depression than female children and growing evidence that these drugs may exac- but after puberty, females have a 1.5–3 fold higher erbate symptoms such as suicidal ideation in child reported rate than males (American Psychiatric and adolescents. In 2003, the FDA issued a public Association, 2013). health advisory about the risk of suicidality in chil- MDD is diagnosed when a person meets five dren taking SSRI antidepressants, which led to the criteria from a list of nine in DSM-5. Practitioners “black box warning” on antidepressants. After this using the International Classification of Diseases point prescription rates for children and adoles- Mental and Behavioral Disorders (WHO, 1992) cents declined (Libby et al., 2007). About 65% of can choose from specifiers of severity based on antidepressants are prescribed for depression and the number of symptoms a client has. Symptoms about 16% for anxiety disorders (Mark, 2010). In in both manuals include vegetative symptoms like the early part of the 21st century, meta-analytic increase or decrease in ability to sleep, increased or studies began suggesting that the efficacy of anti- decreased eating and weight changes, decreased sex depressants is about the same as the placebo, in drive, difficulty concentrating, and anhedonia (loss other words 50%. The efficacy increases as the of pleasure in things the person used to enjoy). The severity of depression in the subjects increases but depressed person may also have inappropriate guilt, there does not seem to be any difference in effi- recurrent thoughts of death, fatigue most of the cacy between the antidepressant drugs (Del Ra, day, and feelings of worthlessness. It is important Spielmans, Fluckiger, & Wampold, 2013; Kirsch to note that we have no clear understanding of & Low, 2013). Some chalk this up to methodo- why the antidepressant drugs covered in this chap- logical problems (Petkova, Tarpey, Huang, & ter would directly reduce the symptoms listed. Deng, 2012) but it is clear there is a strong placebo There are different theories but we have yet to response in studies on antidepressants that needs understand why people get depressed and, when further exploration. medication helps them, why it helps them. That Antidepressants are used both on and off label for said though, we know that the more vegetative numerous disorders. When antidepressant medica- symptoms a client with depression has, the better tions were introduced in the mid-20th century, candidate they are for an antidepressant. We physicians primarily used them to treat depression. should note that it is important to add that depres- Currently, antidepressants are used to treat a variety sion is also part of the symptom profile in many of disorders, including a number of anxiety disor- disorders including Bipolar I Disorder, Bipolar II ders, impulsive aggression, and even chronic pain. Disorder, Persistent Depressive Disorder (previ- Although antidepressants may help people with a ously Dysthymia in DSM-IV ), Schizoaffective Dis- variety of depressive symptoms, most studies on order, Cyclothymia, and Substance Use Disorders. Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 84 PART TWO Introduction COMORBIDITY OF DEPRESSION when pharmaceutical companies started paying to AND ANXIETY have research done on their own medications, they often retained the rights to all results and in many Depression and anxiety, two of the most common cases chose to suppress unfavorable results and rede- symptom types seen by mental health professionals, sign the study to increase the probability of favorable are often comorbid (occur together) in adults as results (Petersen, 2009). That was when the debate well as children. This is so much the case that the began about true efficacy. Researchers began analyz- study groups for DSM-5 considered a Mixed Anxi- ing not just published studies but all studies logged in ety and Depression diagnosis though it did not the FDA database. Based on this initial findings were appear in the final draft. This highlights the impor- that efficacy rates seemed closer to 50% (Armstrong & tance of an accurate diagnosis, because a client may Winstein, 2008). As noted, the debate on efficacy is suffer from depression with some secondary anxi- ongoing but there is a robust placebo response seen in ety, anxiety with some secondary depression, or antidepressant studies that you do not see in studies from both an anxiety disorder as well as a mood treating disorders like Schizophrenia. This may be disorder. Even when a client’s symptoms fall into because depression is overdetermined, meaning there one diagnostic cluster at the time of intake, such a are many ways one could get depressed (Ingersoll & client may later show symptoms outside that clus- Marquis, 2014) whereas Schizophrenia (though we ter. Diagnosis is a process that continues throughout still don’t know its etiology) seems more rooted in the therapeutic relationship and goes well beyond the brain and nervous system. the limited categories of the DSM. Although we focus mainly on depression and antidepressants in this chapter and on anxiety and anxiolytics in Review Questions Chapter Six, these are rather artificial distinctions What are the point and lifetime prevalences for we use for instructive purposes. Just as students Major Depressive Disorder? must learn the “laws” of Newtonian physics before they can understand the exceptions to those laws What conditions are most commonly comorbid that occur in particle physics, they must also learn with Major Depressive Disorder? how classes of medications evolved around diagnos- What are the sex differences in reported rates tic categories and how market and clinical forces of depression? exploit the permeable nature of these classes. In What do meta-analyses suggest the overall the next section, we discuss theories of antidepres- efficacy of antidepressants to be? sant action from the medical model perspective. ANTIDEPRESSANT EFFICACY SECTION TWO: THEORIES OF When an antidepressant “works,” what does that ANTIDEPRESSANT ACTION mean and how does it work? The drug “working” usually means is some but not all symptoms decrease Learning Objectives or go into remission. How the drug works is a harder question to answer. The simple answer is “we don’t Be able to describe the amine, reuptake inhibition and know.” We have theories but we don’t know. It is downregulation theories as they relate to antidepres- sant action. interesting that when we were writing the first edition Understand how each of these theories built on its of this book, published reports of antidepressant effi- predecessor. cacy estimated the drugs worked approximately 65%. Understand the barriers and failed attempts at mea- This figure came from analyzing published results; suring levels of neurotransmitters in the brain. however, as became known in the late 20th century, Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 85 Researchers have sought to delineate profiles of cli- but … this is a typical course of events in psychia- ents with depression, to gauge the degree to which a try, that the discovery of a drug to treat, say, particular client’s depression is biological in nature. schizophrenia, will tend to result in many more They have assumed that clients with depression that patients being diagnosed as schizophrenics. This was more biological in nature would be better can- is strictly Marxian psychopharmacology, where didates for antidepressant medications, whereas cli- the material—or rather, pharmaceutical—means ents whose depression was more psychological in determine the way an individual’s case history is nature would be better candidates for counseling or interpreted. (p. 265) psychotherapy. As Stahl (2000) concluded, however, “The search for any biological markers of depression, Amine Theory let alone those that might be predictive of antide- The amine theory of depression began as the pressant responsiveness, has been disappointing” catecholaminergic hypothesis of depression (p. 145). Today, the field of pharmacogenetics aims proposed by Ernst Albert Zeller and his research to match antidepressant response to idiosyncrasies of team (Zeller, Barsky, Fouts, Kirchheimer, Van client’s genomes but this research has just begun and Orden, 1952). Catecholamines are organic com- it remains to be seen if it will bear results that are pounds derived from the amino acid tyrosine and applicable (Jones & Perlis, 2006). include the neurotransmitters norepinephrine (NE), How do antidepressants work? Various theories dopamine (DA), and epinephrine (Epi). A broader from the medical model perspective are proposed to chemical class is the amines that are compounds explain antidepressant action. Each tends to build on derived from ammonia by replacing one or more its predecessors. In this sense, these theories actually hydrogen atoms with organic groups. The neuro- demonstrate one of the ideals of scientific method— transmitters serotonin (5-HT), DA, NE, Epi, and new theories ideally are built on older theories. How- acetylcholine (Ach) are all amines. Thus, as soon as ever, although these theories do build on one another, researchers began to suspect serotonin (5-HT) played scientists still do not understand why antidepressants a role in depression the catecholamine hypothesis alter mood. Perhaps Healy (2002) captured the ulti- was made broader into the amine hypothesis. mate usefulness of theories when he stated, “[H]aving The amine hypothesis began with researchers a theory is scientifically useful primarily because hav- observing the effects of antidepressants on norepi- ing a theory leads to action” (p. 118). In this case, the nephrine. Simply put, the amine hypothesis proposed action depends on the theory. From an integrative that people who suffered from depression did not perspective, we will see that even rigorous theories have enough amines, particularly NE, in their syn- of how antidepressants work only correlate the drug apses, and if you could increase the NE then they mechanisms of action with symptom relief. It must be would not be depressed. It was a parsimonious the- noted, however, that this correlation is not causation. ory and, as with most parsimonious theories, it did In the case of depression, many times the theories not address the complexity of the situation. It is about medications lead to diagnoses rather than the important to note though that researchers in the other way around. This has been emphasized both mid-20th century can be forgiven for adhering to by psychiatrists with knowledge of pharmacology the overly simple amine hypothesis because at that (such as Healy) and by laypeople such as Elizabeth point all they knew about the drugs was that they Wurtzel. In her memoir of suffering from depression, somehow increased amines. Wurtzel (1994) commented that once she was pre- The first step in the amine hypothesis is credited scribed Prozac, she had a diagnosis. She wrote, to Ernst Albert Zeller (mentioned above) who was Rather than defining my disease as a way to lead working as a biochemist at Northwestern Univer- us to fluoxetine, the invention of this drug has sity in the 1950s. Zeller and his research team had brought us to my disease. Which seems backward, discovered that one function of the enzyme Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 86 PART TWO Introduction monoamine oxidase (MAO) was to disable neuro- symptoms while on reserpine/Serpalan (Akiskal & transmitters after they had been fired from the ter- McKinney, 1973). Again, to clarify, the amine the- minal button (Zeller et al., 1952). This made sense ory of depression was that people who are because scientists knew neurotransmitters did not depressed do not have enough amines (such as nor- just float in the synapse forever and that the body epinephrine) in the synapses between important must have a way to disable them. While screening neurons. Drugs that increased the amines thus alle- chemicals for this disabling ability, Zeller found that viated depression. iproniazid/Marsilid (the antitubercular drug Nathan To this point, this first MAO inhibitor (iproniazid/ Klein used as an antidepressant) was a powerful Marsilid) had only been used to treat tuberculosis. It inhibitor of MAO (thus the name MAO inhibitor) was noticed that the drug also had power to stim- (Snyder, 1996). Further research confirmed that ulate the CNS in patients being treated. This was iproniazid/Marsilid, by disabling MAO, did indeed initially thought to be a side effect (Selikoff, Robit- raise NE levels in the synapse. In 1957, Udenfriend, zek, & Ornstein, 1952). This then led Jackson Weissback, and Bogdanski (1957) observed that Smith (1953) to try the drug on depressed patients. iproniazid/Marsilid also increased the release of They noted improvement in 2 of the 11 in the serotonin (5-HT) in the brain. group and other studies followed [it is thought It is widely believed that scientists at the time that one of the later researchers, Max Lurie, coined used a drug called reserpine/Serpalan to deplete the term antidepressant (Lopez-Munoz & Alamo, the brain of amines and cause an animal model of 2009)]. Nathan Klein carried out the same proce- depression. The story is that researchers gave both dures on subjects and reported that 70% showed reserpine/Serpalan and iproniazid/Marsilid to mon- substantial improvement (Loomer, Saudners, & keys. First the reserpine/Serpalan made them Kline, 1958). Given that the response rate in appear lethargic and fatigued (the animal model of Smith’s study was only 18%, it is curious that depression) and then the iproniazid/Marsilid led the response rates in Klein’s studies rocketed to 70%. monkeys to become highly animated. This then led To date we are not aware of any re-analysis of this to the notion that perhaps iproniazid/Marsilid was early work. Be that as it may, iproniazid/Marsilid, a psychic energizer (Snyder, 1996) or what the was on the map as an antidepressant. reserpine research team called a “marsilizer” refer- Tricyclic antidepressants evolved in Europe ring to the trade name of the compound (Lopez- through the work of Roland Kuhn (1958) about Munoz & Alamo, 2009). This was found to be the same time MAO inhibitors were developing more speculation than fact on the part of Nathan in the United States. Given the MAO research, Klein (1970) who popularized the MAO Inhibitors Kuhn and his colleagues thought tricyclics worked for their antidepressant properties (Baumeister, in the same way, by disabling MAO or some related Hawkins, & Uzelac, 2003). enzyme and increasing NE in the synaptic cleft. Researchers later discovered that reserpine/ The clinical actions of both drugs, after all, were Serpalan did cause both norepinephrine and seroto- quite similar. This assumption soon ran into pro- nin to leak out of the synaptic vesicles into the blems, however, when researchers discovered that synaptic cleft, where MAO disables it. Thus, dis- much of the MAO in the nervous system exists abling MAO greatly increases the newly leaked inside the cells rather than in the synaptic cleft. norepinephrine and serotonin in the synaptic cleft, Also, all antidepressants seemed to have a time lag allowing more binding to area receptors than does of at least two weeks before they took effect. This an undrugged state. These discoveries (exaggerated didn’t make sense, because MAO began to inhibit though they seem to have been) were the primary iproniazid within hours after the patient took the support for the amine theory. Historical review of first dose. the reserpine/Serpalan studies revealed that in actu- As noted, the amine theory proved too parsimo- ality only a subset of patients developed depressive nious. For one thing, the idea of depressed clients Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 87 being deficient in a neurotransmitter should corre- longer in the synaptic cleft. For his work in this late with lower levels of the metabolite for the neu- area, Axelrod shared the 1970 Nobel Prize in Medi- rotransmitter they are supposed to be lacking. cine with Ulf von Euler and Sir Bernard Katz. (It is Although some subjects in studies show this corre- one of the few Nobel prizes awarded for work lation, others do not. Stahl (2000) noted that when related to psychotropic medications because most the metabolite for serotonin (5-HT) is low, it is discoveries in the area of psychotropic medications more likely correlated with impulsive behavior are more luck and serendipity than the result of care- than with depression proper. Plus, the amine theory fully crafted hypotheses). did not explain why it took the antidepressants four Nevertheless, the same time lag noted for to six weeks to work. MAO inhibitors existed with tricyclic antidepres- sant drugs that inhibited reuptake. For example, The Discovery of Reuptake Inhibition about an hour after the person takes a tricyclic antidepressant the reuptake inhibition begins and The next researcher to make important discoveries the amount of neurotransmitter in the synaptic in this area was Arvid Carlsson who discovered how cleft increases, but symptoms do not abate for tricyclics blocked reuptake of serotonin at the brain between two and four weeks (maybe even as level (Carlsson, Fuxe, & Ungerstedt, 1968). After long as six weeks). So, despite making important this discovery, Izyaslav Lapin and Gregory Oxenk- contributions to the understanding of reuptake rug (1969) postulated the serotonergic theory of inhibition, Axelrod had not solved the riddle of depression, similar to the amine theory only focus- how tricyclic antidepressants actually work to ing on serotonin rather than norepinephrine. In the change mood. 1950s, working at the National Institutes of Health in Bethesda, Maryland, Julius Axelrod discovered that with tricyclic antidepressants, norepinephrine Downregulation Theory was increased in the synaptic cleft when the drug Although enzyme deactivation and reuptake inhi- inhibited the reuptake mechanism discovered by bition are important elements in most antidepres- Carlsson. The mechanism works like this: When sants’ mechanism of action, they still don’t account norepinephrine is released into the synaptic cleft, for the two- to six-week lag of the antidepressant it has a period of time to bind to receptors. After effect. The reuptake properties of tricyclic antide- this period, it is either broken down by MAO or a pressants and selective serotonin reuptake inhibitors transporter molecule attaches to the NE neuro- begin increasing levels of neurotransmitters within transmitter and takes it back inside the cell that an hour of someone’s taking the medicine. Another released it in the first place, where enzymes store problem is that other drugs that dramatically boost it in synaptic vesicles so it can be released again. In the levels of similar neurotransmitters (cocaine) do this way, the transporter molecule provides some- not act as antidepressants. Although they may thing like a recycling service. induce euphoria, they also cause an emotional Other researchers have identified a similar mech- “crash” when the drug wears off. This knowledge anism for most other neurotransmitters, with the contributed to the development of postsynaptic exception of acetylcholine, which is deactivated by receptor desensitization (downregulation) theory the enzyme acetylcholinesterase (just as norepineph- as a complement to the amine theory. This theory rine can be deactivated by monoamine oxidase). proposes that initially the receptors in the depressed This discovery only served to reinforce the amine person are hypersensitive to neurotransmitter theory of depression, because researchers eventually because depressed people have less of that neuro- discovered that drugs such as tricyclic antidepressants transmitter (remember these are just theories that work by inhibiting this reuptake mechanism and were partially but not totally accurate). Because thus allowing released neurotransmitters to stay there was supposedly less neurotransmitter, the Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 88 PART TWO Introduction researchers hypothesized that receptors act as if they of antidepressants nor that there was any “chemical are “starved” for it, so they upregulate (increase in imbalance” that caused depression. To be clear, number). (Remember, this is a theory using there is no direct way to measure an extracellular metaphors—not concrete truths. In the metaphor level of any neurotransmitter in the human brain. used to explain this theory, receptors are not really Some postmortem studies on the brains of people “starved” for a neurotransmitter but if they had who committed suicide suggested there were low human qualities one might say they would act as levels of 5-HT in the brain stem tissue but without if they were. Such anthropomorphizing of things a baseline it is not possible to say what is “low.” like neurons is replete with ways it can be misun- Also the amount of 5-HT in tissue is not necessarily derstood). With antidepressant treatment, as more reflective of extracellular amounts (amounts in the neurotransmitter becomes available, the receptors synapse) (Jacobson, Medvedev, & Caron, 2012). get more neurotransmitter than is needed because For decades, researchers have probed the brain they previously increased in number (upregulated) with indirect measures looking for biomarkers of to make use of the available neurotransmitter in the 5-HT. Cerebrospinal fluid (CSF) levels of the 5- synaptic cleft. At this point, the cell gets bombarded HT metabolite 5 hydroxyindoleacetic acid (5- with neurotransmitter, because the increased levels HIAA) have been thought to reflect brain levels of of neurotransmitter are now binding with the 5-HT but the correlations between lower levels of increased numbers of receptors. The theory sug- this metabolite are more consistent with things like gested that the cells then adjust by decreasing the aggression, suicidality and impulsivity than depres- number and sensitivity of receptors, because more sion (Placidi et al., 2001). neurotransmitter is available. Theoretically, this There have been so-called challenge methods normalizes transmission or provides the “balance” where 5-HT in the central nervous system is chal- that is correlated with decrease of symptoms. So lenged with another agent and the resulting changes according to downregulation theory, the antide- in things linked to 5-HT have been observed. For pressant effect is the result of two mechanisms. example, fenfluramine/Pondimin has been used in The first is the increase of neurotransmitter depressed subjects in this manner. Fenfluramine/ released into the synapse (accomplished through Pondimin stimulates 5-HT to trigger secretion of reuptake inhibition or enzymatic inhibition), and prolactin. The prolactin is measured and a blunted the second is the downregulation of receptors to a response was thought to reflect low 5-HT level and “normal” level of responsiveness (to adapt to the a robust prolactin response to reflect a high 5-HT increased levels of neurotransmitter). The time level (Mann, McBride, Malone, DeMeo, & Keilp, frame required for neurons to decrease the num- 1995). The problem with this is that the triggering ber of receptors correlates closely with the lag of prolactin secretion is a complex process involving time between taking a drug and experiencing not just 5-HT but gamma-amino-butyric acid the antidepressant effect (two to six weeks (GABA), peptides, and oxytocin (Emiliano & depending on the client and dosage of medica- Fudge, 2004). As these examples illustrate, “… the tion) (Stahl, Hauger, Rausch, Flieshaker, & association of 5-HT deficiency, or any other singu- Hubbell-Alberts, 1993). lar biochemical anomaly, with major depression as The downregulation theory led researchers to the all-encompassing syndrome is inconclusive” consider the role of receptor sensitivity in mental/ ( Jacobson et al., 2012). emotional disorders. This combination of the amine Variations on these theories were proposed, such theory and downregulation theory was used to as the permissive theory, which restated the amine account for the action of antidepressants until very hypothesis but included serotonin rather than recently. Remember, these were and still are just exclusively focusing on norepinephrine. The per- theories. Researchers never had conclusive evi- missive theory also tried to explain the role of sero- dence that the theories fully explained the function tonin in regulating levels of norepinephrine and Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 89 dopamine. Although all these theories expanded SECTION THREE: THE NEUROTROPHIC/ available data on antidepressant action, none fully PLASTICITY HYPOTHESIS AND accounted for antidepressant effects or the strong placebo responses in many studies of antidepressants NEW THEORIES OF (we return to these later). The latest hypothesis to ANTIDEPRESSANT ACTION explain antidepressant effects takes the discussion deeper into the mysteries of the cells called neurons, as we describe next. Learning Objectives Be able to articulate the basic steps in the neuro- Neurotransmitter Receptor trophic/plasticity theory of depression and antidepres- Hypothesis sant actions. The neurotransmitter receptor hypothesis asserts Have a general understanding of signaling pathways that in depression, something is wrong with partic- in cells and how they may figure into antidepressant action. ular receptors for monoamine neurotransmitters. Be able to give an overview of the neuropsychological Researchers think this “something wrong” leads theory of antidepressant action and re-learning in to depression. It is also related to the upregulation recovery from depression. of receptors discussed earlier. Because this hypothe- sis focuses on the receptors and because receptors are a function of gene expression, this hypothesis The neurotrophic/plasticity hypothesis began as also considers that depression may relate to some the cellular/molecular theory of antidepressant function (or malfunction) of gene expression. Cer- action (Duman, Heninger, & Nestler, 1997). This tainly this is a possibility; however, where genetics required advances in medical technology that is concerned it is important to state hypotheses ten- allowed scientists to peer inside neurons. The result tatively and concisely to avoid lapsing into word is a theory that transcends the other theories outlined magic. Although admitting that direct evidence to so far. At the outset, we want to stress that this is support the genetic hypothesis is lacking, Stahl unlikely to be the final word on the biological theo- (2000) discusses the previously outlined postmor- ries of depression, because it also leaves many ques- tem studies of the brains of suicide victims where tions unanswered. test results show that the tissue in parts of these The cellular/molecular theory of depression was brains have increased numbers of 5-HT2 receptors. first outlined by Duman et al. (1997). In a sense it is He concludes that further research may support a a metatheory, in that it encompasses and transcends genetic variation of the neurotransmitter receptor its predecessor theories in a way that it is a theory hypothesis. about the previous theories. The authors begin by summarizing the complementarity of amine theory Review Questions and downregulation theory, noting that these the- ories accurately outline certain actions of antide- What are the theories of amine theory, reup- pressants but fail to explain why such actions take inhibition, and downregulation, and how would improve mood. They then assert that do they relate to antidepressant action? increases in the levels of available neurotransmitters How did each of the theories in question (1) and the resulting downregulation are merely the build on each other? beginning of antidepressant action. Next they doc- What efforts have been made to measure ument intracellular changes in response to someone neurotransmitter levels in the brain? Why have taking antidepressant medications. Note that these these failed? authors maintain that once a person takes an anti- depressant medication, these intracellular changes Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 90 PART TWO Introduction occur after the drug increases the neurotransmitter suffering from Parkinson’s disease. These patients levels and persist after downregulation. These experienced dramatic decreases in their symptoms authors explain that within the cell, antidepressants (Schorr, 2004). It has also been shown that infusion cause an increase in cyclic adenosine monopho- of BDNF into the hippocampus of rats produced sphate (cyclic AMP or cAMP). Cyclic AMP is a what appeared to be antidepressant effects (Hurley second messenger molecule with many functions. et al., 2013). Such work may hold promise for men- Some of these functions are activating enzymes in tal and emotional disorders that have clear biological the neuron, amplifying the effects of hormones and correlates, but those correlates must be conclusively neurotransmitters, and providing other vital func- determined. tions in the cell. The cAMP levels raised by taking The following flow chart summarizes these the- antidepressants apparently do not return to lower ories of depression and how each one builds on levels as the person adjusts to the presence of the previous ones. drug. Interestingly, cAMP governs the production and processing of neurotrophins called brain-derived neurotrophic factors (BDNFs). BDNF is a neurotro- Amine Theory: phin in the brain that plays an important role in Depression is caused by a regulating neurogenesis (creation of new neurons), shortage of particular neurotransmitters (NTs). Doesn’t explain lag time in treatment. differentiating neural pathways during neurodeve- lopment, and modulating synaptic plasticity as well as dendritic growth. So after administration of antidepressants, as cAMP increases in response to the antidepressant Reuptake Inhibition: Complements amine theory by explaining how medication, these neurotrophins (BDNF) also the NTs are increased by taking tricyclic antidepressants. increase. You can think of the neurotrophins as Still doesn’t explain time lag in treatment. akin to brain cell nutrients in that they trigger changes associated with neurogenesis and mainte- nance of existing neurons. Many of the changes following antidepressant treatment occur in the Downregulation Theory: hippocampus, which is part of the limbic system. Complements latter theories by offering an explanation Without unpacking all the molecular biology of why therapeutic effects of antidepressants involved, let’s say the basic idea is that the cell goes take two to six weeks to start. through many changes after an antidepressant is introduced into the system and that the increase in neurotrophins (cell nutrients) may be one of the most important. The developers of the cellular/ Neurotrophic/plasticity Theory: molecular theory of depression are proposing that Gives a view from inside the cell of the types of stress and disease processes cause neurological atro- intracellular changes correlated with the downregulation and onset of therapeutic effects of antidepressants. phy ranging from reversible to irreversible. One manifestation of this hypothesized atrophy is depres- sion. Such damage may be reversed by an increase in cell nutrients that is one of the many results of taking Not only does the neurotrophic/plasticity theory an antidepressant medication. Brain-derived neuro- of depression hold promise for providing a fuller trophic factor holds promise for treating degenerative understanding of how antidepressants work, it also brain disorders such as Parkinson’s disease. In a recent promises a fuller understanding of nonpharmacologic study in the United Kingdom, researchers injected approaches to treating depression. Scientists have neurotrophic factor directly into the brain of patients known for some time that physical exercise is effective Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 91 in reducing depressive symptoms (De Melo Coelho like depression and anxiety (Kourmouli et al., 2013). et al., 2013; Salmon, 2001). Researchers have already This is the type of research necessary to address the documented that general physical exercise rapidly complexity of how genes may contribute to devel- increases brain-derived neurotrophic factors (Russo- oping symptoms like depression. Neustadt, Beard, & Cotman, 1999). In studies using brain scan technology, depressed participants taking an The Emerging Science of the Role of antidepressant medication and depressed participants Signaling Pathways in Depression engaging in interpersonal therapy showed similar We have already noted that antidepressants seem to changes in their brain scans as their depression increase cAMP, which then increases BDNF. We improved. Although the therapy group took longer have further learned that there is signaling pathway to manifest these changes, they were as significant as for cAMP that may be pivotal in therapeutic the changes in the group taking the antidepressant response to antidepressants. We noted that cAMP (Brody et al., 2001). Apparently exercise and is a second messenger that has many functions counseling/psychotherapy may induce the same including transferring into cells the effects of hor- types of intracellular changes as antidepressants. If mones that cannot pass through the cell membrane. future research supports this hypothesis, it is important There are also multiple signaling pathways used by for counselors and other mental health professionals to cells to regulate cellular processes. cAMP also qua- understand, because this radically expands a client’s lifies as one of these. In the cAMP pathway, cAMP treatment options. This is also why we emphasize activates molecules called effectors that bind to pro- an integrative openness regarding the mind–brain teins to regulate their biological activity. issue in this book: Mind—intention, attention, One effector that may play a role in antidepres- and awareness—may well be as effective—or more sant effects is protein kinase and in particular on fam- effective—than pharmacologic interventions. ily of enzymes labeled protein kinase A (PKA). It seems that PKA activity is increased after four to six weeks of antidepressant treatment. PKA activity NEWER HYPOTHESES AND THEORIES in turn activates the cAMP response element binding Since the advent of the neurotrophic/plasticity the- protein (CREB), which is a transcription factor (a ory, researchers have learned many new things protein that binds to specific DNA sequences). about how antidepressants seem to work in the This in turn affects the expression of several genes brain. First, BDNF has been traced to genes. The involved in cell survival, neuroplasticity, and cogni- gene for BDNF is on chromosome 11 and is about tion. Again we can see that the more current theories 1300 letters long. In most animals, letter 192 is “G” of antidepressant action are increasingly sophisticated (for guanine) but in some it is “C” (cytosine). This regarding how complex the human nervous system causes a slightly different protein to be built with is compared to earlier theories like the amine theory. methioline rather than valine at the 66th position. CREB has been implicated in both depression and Thus, with regard to the gene for BDNF there are antidepressant treatments (Pilar-Cuellar et al., 2013). three types of people in the world: The implication is that things that affect cAMP and BDNF have ripples far down the signaling pathway 1. Val-vals increasing the variables that may play a role in alle- 2. Val-mets viating depression whether the client is involved in 3. Met-mets antidepressant therapy, exercise, or psychotherapy or In research on the five-factor model of personal- all of the above. ity, the most neurotic to least neurotic are suppos- The next pathway that may play a role in anti- edly val-vals (most neurotic), val-mets, and met-mets depressant response is called the Wnt/B-Catenin (least neurotic). Thus, building BDNF proteins with pathway (Wnt). The Wingless-type family of pro- methioline may serve a protective factor from things teins play key roles during neurodevelopment like Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 92 PART TWO Introduction neural differentiation, formation of the hippocam- 18-month follow-ups, many clients who respond to pus, dendritic arborization, axon guidance, and for- antidepressants report that the antidepressants stop mation of synapses. On a larger scale, this family of working. This is given the highly technical name proteins plays a role in memory and spatial learning “pooping out.” The percentage of clients whose (Pilar-Cuellar et al., 2013). Wnt is also implicated antidepressants “poop out” after 18 months is as in the etiology and treatment of depression high as 20 to 30% in some studies. (Hernandez, Nido, Avila, & Villanueva, 2009). In the absence of Wnt signaling, important functions TOWARD AN INTEGRATIVE THEORY in the cell are blocked by glycogen synthase kinase- 3 and other ligands. This “blocking” seems undone OF ANTIDEPRESSANT ACTION in some (but not all) clients with antidepressant and It seems that as our technologies improve, we are so-called mood-stabilizing medications (Jope & peering deeper and deeper into the brain, the neu- Bijur, 2002). rons, glial cells, and the universe within each cell. A third pathway that may be important in antide- At some point, it is reasonable to ask how far down pressant treatment is called the mTOR pathway and this path we can go and get results. At some point, is related to rampamycin genes. Thus, the abbrevia- we will reach the subatomic level and will we yet tion mTOR is derived from the original name for have a complete picture of depression and antide- this pathway “mammalian target of rampamycin.” pressant action? Some theorists are positing an inte- This pathway is important in apoptosis (cell death) grative approach that moves from the top down and and has mainly been studied in cancer, and a number the bottom up. The “bottom up” part is the theo- of neurological diseases like Alzheimer’s-type demen- ries of antidepressants that we have covered thus far. tia. Recent studies associate mTOR signaling in The “top down” is a new theory called the cogni- depression because of the fast-acting effects of keta- tive neuropsychological theory of antidepressant mine (discussed below) as an antidepressant (Mathew, action. Keegan, & Smith, 2005). This theory was laid out in the context of selec- Reviewing physiological theories of how antide- tive serotonin reuptake inhibitors (SSRIs) but can pressants work can be dizzying as well as impressive. be generalized across antidepressants. The basis of The key is to not forget that although these theories the theory is this: that depression comes with a encompass truths about antidepressants and depres- negative cognitive bias and antidepressants, even sion, they are only partial truths. These theories give after only one day of treatment, are correlated us important truths from the medical model perspec- with a decrease in negative bias and an increase in tive. However, they are only partial truths; resist the positive bias (Harmer & Cowen, 2013). This theory temptation to simplify the complexity of something can be traced back to Crews and Harrison (1995). such as recovering from depression with word magic The essence of the idea is that people who are claiming that antidepressants corrected a “chemical depressed show a negative emotional bias that has imbalance.” When clients respond to antidepressants, sometimes been called “depressive realism” because that response is only partial in some cases. As Ross they are more accurate at picking out negative real- (1995) pointed out, even in those studies up to 30% ities than “healthy” controls (Kronbrot, Msetfi, & of the clients may respond to placebo, but this find- Grimwood, 2013; Moore & Fresco, 2012). The ing is never systematically followed up. Finally, Stahl neuropsychological theory of antidepressant action (2000) noted that in terms of recovery, follow-up suggests that the time lag for therapeutic effect (two studies of depressed clients after one year of treat- to six weeks) may be as much a function of time ment indicate that approximately 40% still meet spent “re-learning” how to interpret life events as the criteria for the same diagnosis and 20% never much as a physiological process. There are studies recover fully or meet the criteria for dysthymia comparing depressed people with normal controls (low-grade depression). Further, Stahl notes that in and testing their interpretations of faces they are Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.  CHAPTER FIVE The Antidepressant Era 93 shown. The depressed people are more likely to In this section of the chapter, we convey a more judge a facial expression negatively than the con- standard presentation of the antidepressants. It is trols (Beck, 2008). difficult to make global statements about the effi- Interestingly, even in studies where nondepressed cacy of antidepressants in general; however, the lit- controls are given antidepressants, a statistically sig- erature does seem to agree that all the different nificant percentage have an increase in expressed classes of antidepressants are about equally effective. positive bias (Harmer et al., 2003). This seems to Stahl (2000) summarized this agreement, noting it is be the case except when the antidepressant is admin- a “good news/bad news” scenario. The good news istered intravenously. Because we know antidepres- is that 50–60% of depressed clients on any antide- sants promote synaptic plasticity in animal models, it pressant respond positively to it, and even more may be that the antidepressants are providing a may respond if tried on several different com- chemical “window of opportunity” for the clients pounds. Half of these responders may progress to rewire their experience through experiencing a into full remission within six months of treatment. more positive bias. This raises more ethically tricky In addition, antidepressants seem to significantly questions like would drugs that seem relatively reduce relapses as well. The bad news is that harmless like cannabis and induce positive mental many responders never reach full remission and states also function as antidepressants? that in 20 to 30% of the people who respond at all to antidepressants, the effects tend to “poop out” or wear off after about 18 months. Review Questions Although Stahl emphasizes the medical model Describe the additions of the neurotrophic/ perspective of depression, equating it with diabetes plasticity theory to amine, reuptake and or hypertension, the “bad news” merely means that downregulation theories—specifically— in some cases biological interventions are time lim- describe what happens with cAMP and BDNF. ited. This is only truly “bad news” if in fact there What is the healthiest genetic combination for are no other treatments for depression, which is not hearty BDNF? the case. Given that many people don’t maintain their response to antidepressants, it makes sense to Describe how the neuropsychological theory of view a response as a time-limited window of antidepressants could bring the best of the opportunity within which to employ an integrative pharmacological and psychotherapeutic worlds approach to treatment. An integrative approach together. uses all the perspectives we have been discussing in this book. SECTION FOUR: OVERVIEW OF The Role of Vegetative Symptoms FIRST-GENERATION ANTIDEPRESSANT In the treatment of MDD, note that the more vegetative symptoms a client suffers from, the MEDICATIONS better candidate the person is for antidepressant med- ication, because these symptoms are most affected by Learning Objectives the medication. Maybe because depression is over- determined (meaning it may be caused by biological, Understand how vegetative symptoms are important psychological, cultural, social, and perhaps even spir- to gauge therapeutic response. itual factors), a preponderance of vegetative symp- Be able to describe the primary mechanisms of action for MAO Inhibitors and Tricyclic Antidepressants. toms point toward a stronger biological component in etiology. Table 5.1 contains a list of common Know the potential side effects for MAOIs and TCIs. vegetative symptoms for MDD. Copyright 201 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 94 PART TWO Introduction TABLE 5.1 Common Vegetative Symptoms in TABLE 5.2 Examples of MAO Inhibitor Anti- Major Depressive Disorder depressants and Common Daily Dosage Ranges Sleep disturbance (early morning waking, frequent Common Daily awakening, occasional hypersomnia) Dosage Range Generic Name Brand Name Appetite disturbance (decreased or increased appetite Selegiline L-Deprenyl 10 mg with accompanying weight fluctuations) Isocarboxazid Marplan 20–50 mg General fatigue Moclobemide Manerix 150–500 mg Decreased sex drive (available in Canada) Restlessness, agitation, or psychomotor retardation Phenelzine Nardil 30–75 mg Diurnal variations in mood (usually feeling worse Tranylcypromine Parnate 20–40 mg in the morning) © Cengage Learning® Impaired concentration and forgetfulness Thus, the chemical bond of the MAO inhibitor Pronounced anhedonia (loss of pleasure in mos