Mood Stabilizers PDF

C H A P T E R E I G H T Mood Stabilizers Bipolar I Disorder (BPI) is an incapacitating, severe I Disorder. Section Six covers newer treatments like mental il...

C H A P T E R E I G H T Mood Stabilizers Bipolar I Disorder (BPI) is an incapacitating, severe I Disorder. Section Six covers newer treatments like mental illness that affects approximately 1% of the lamotrigine/Lamictal. Section Seven takes us back to population (APA, 2013). It usually has its onset in the atypical antipsychotics and details their use in adulthood and early onset is age 13. Despite this, Bipolar I Disorder. Finally Section Eight discusses cul- there has been an epidemic of misdiagnosing chil- tural and social issues related to mood stabilizers. dren who act out as having Bipolar I Disorder. In an effort to stem the tide of misdiagnoses, the SECTION ONE: MOOD MISNOMERS American Psychiatric Association (APA) included an untested, new diagnosis in DSM-5. It is called Disruptive Mood Dysregulation Disorder and deals Learning Objectives with acting out, aggressive behavior, and tantrums Understand the history of the phrase “mood that are developmentally abnormal as defined by stabilization.” the criteria. The consensus now is that for a child Be able to state what makes a drug a good mood to be diagnosed with Bipolar I Disorder she or he stabilizer. must show evidence of sustained, inappropriate euphoria and grandiosity. We discuss this further in Chapter Nine but the context of mood stabilizers The very phrase “mood stabilization” is curious. is changing radically and we hope, in this chapter, Webster’s New Universal Unabridged Dictionary to not just introduce you to the medications that (1989) notes that a stabilizer makes or holds things are grouped under the mood stabilizer category, but stable. That is simple enough, but the very nature of also help you understand the rapidly changing con- mood in us human beings is rarely stable. In fact, our text of diagnosing and treating Bipolar I Disorder. range of affect and the manner in which we express This chapter is divided into eight sections. The it may be one of the hallmarks of being (or becom- first explores the curious history of the phrase ing) human. Clinically speaking, “normal” mood is mood stabilizer and discusses what an effective referred to as a state of “euthymia.” This word, mood stabilizer should do. The second section cov- however, has two slightly different meanings. The ers an overview of Bipolar I Disorder and its symp- more clinical meaning of euthymia is a state that toms. Section Three provides some history on how is neither manic nor depressed. Simple enough— some of the medications in use were discovered and perhaps too simple where human beings are con- developed. Section Four focuses on lithium, the first cerned. A more important meaning of “euthymia” drug used specifically for Bipolar I Disorder or what is rooted in the etymology of the word (almost never used to be called Manic-Depressive Illness. Section referred to by mental health clinicians). The original Five discusses anticonvulsants used to treat Bipolar Greek meaning of euthymia is being “tranquil or 187 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. 188 PART TWO Introduction joyous.” Eu- is a Greek prefix meaning “good or of joy is perhaps reflected in the severe restriction of well,” and thymus refers to “mind.” Unfortunately, access to those drugs that actually seem to induce joy. clinicians typically restrict the word euthymic to the More often, clients taking mood stabilizers report shallower, clinical meaning, of “neither manic nor feeling constricted mood, something even less than depressed.” Perhaps we would better serve clients if the normal fluctuations of mood. Clinically, such we aimed for the original meaning. Imagine what clients are described as being neither manic nor mental health delivery would be like if joy and tran- depressed, but many tell us this is not a pleasant quility were viewed as desirable goals for clients! As state. What does it mean to feel neither manic nor philosopher Alan Watts (1973) noted, mental health depressed? Describing a state by what it is not [called clinicians seem to be suspicious of things such as joy the via negativa or apophatic (without images) in the and prefer that consensual reality be defined as the spiritual logic of St. Thomas of Aquinas] usually fails frame of mind one has going to work on Monday to give a clear picture of what the state really is. We morning. Be that as it may, mood stabilization is the suspect that the clinical meaning of euthymia is per- practice of introducing pharmacologic agents that keep haps more word magic retreated to by exhausted clients’ moods within parameters clinically described as clinicians who simply want to say, “The client is nei- “normal” or “euthymic.” The psychotropic agents ther manic nor depressed.” So we are somewhat back used to do this are called mood stabilizers. where we started. The phrase “mood stabilizer” was first used in In an effort to operationalize for readers the myste- 1985 by Guy Chouinard who suggested that com- rious phrase “mood stabilizer,” we use the parameters bining estrogen and progesterone may create a mood set by clinical logic and draw on the work of Schou stabilizer (Healy, 2008). The phrase mood stabilizer (1997) and Keck (Interactive Medical Networks, did not come into use until the mid-1990s and it 2001). Schou noted that a mood stabilizer should have was not a phrase scientifically gleaned from years of far-reaching effects. Ideally, it should show efficacy for painstaking research on how certain drugs affected relieving manic episodes and depressive episodes, and patients. No, it was pressed into use by Abbott Lab- as a prophylactic treatment, for preventing any further oratories marketing their newly patented Depakote/ severe mood symptoms. Keck agreed, noting that valproic acid (Healy, 2013). Depakote was approved mood stabilizers should (1) show efficacy in an acute for the manic phase of Bipolar I Disorder in 1995 but, manic phase, (2) show such efficacy in one stage of as Healy (2013) points out, this is not surprising Bipolar illness without exacerbating another stage, because any sedating drug will produce a change in and (3) show some efficacy for mood, psychotic, and people suffering from mania. At the time there were cognitive symptoms. Keck also added that mood sta- relatively few manic patients and many sedatives on bilizers should show some efficacy as a prophylactic the market. Abbott’s license did not allow them to (Interactive Medical Networks, 2001). The key to claim Depakote would stop mood swings or act as a these definitions is that an ideal mood stabilizer does prophylactic. They dealt with this by emphasizing more than simply calm a person suffering from mania. the ambiguous phrase “mood stabilization” in their That calming could easily be accomplished with one marketing of Depakote. It was ambiguous enough to of the benzodiazepines described in Chapter Six or be the perfect marketing term. Even psychiatry one of the neuroleptics described in Chapter Seven; began using it and admitting that as a field, psychiatry however, the neuroleptic would have little impact on did not really know what it meant (Sobo, 1999). the depressive symptoms or as a prophylactic. There were no peer-reviewed papers on “mood sta- Clinically, the words used to describe mood disor- bilizers” in 1990 and over 100 in 2000 (Healy, 2013). ders are important for understanding mood stabilizers. Regrettably, as you will see, these so-called We all need to understand the terms bequeathed to us mood-stabilizing agents rarely bring clients the dee- from DSM-IV to describe mood symptoms that may per experience of euthymia, described by the ancient require mood stabilization. Although DSM-5 has Greeks as tranquil or joyous. In this society, suspicion changed “Mood Disorders” to two separate categories 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 EIGHT Mood Stabilizers 189 Major Depressive Low Grade Hypomanic Manic Episode Depression Euthymia Episode Episode Major Depression Dysthymia Cyclothymia © Cengage Learning® Bipolar II Bipolar I FIGURE 8.1 The Pendulum Metaphor of Mood Disorders (Depressive and Bipolar Disorder), this exercise is still next descriptor is “manic episode.” This is mood so useful. Figure 8.1 offers the metaphor of a pendulum elevated that it is “sufficiently severe to cause marked to illustrate these concepts. impairment in social or occupational functioning or As you can see in Figure 8.1, euthymia is at the to necessitate hospitalization to prevent harm to self pendulum’s center, implying a “centered” state, or others” (American Psychiatric Association, 2013, meaning normal. In the figure, elevated mood is p. 124). In the direction of depressed mood, there is a shown as movement to the right of euthymia and low-grade depression spectrum referred to in DSM depressed mood is shown as movement toward the first as Persistent Depressive Disorder (previously left of euthymia. Mood elevated above normal is not Dysthymia in DSM-IV ) and finally Major Depres- described as pathology in DSM even when it reaches sion, described in Chapter Five. Figure 8.1 includes hypomanic levels. Hypomanic episodes were new in arrows, spanning the range of a client’s mood, that DSM-IV (American Psychiatric Association, 1994), correspond to DSM criteria for particular disorders. have been retained in DSM-5 (APA, 2013) and Mood stabilization comes into play in Cyclothymia remain difficult to diagnose. The primary difficulties (fluctuations between hypomania and persistent lie in confirming the symptoms and in the fact that depressive disorder), Bipolar II Disorder (fluctuations hypomanic symptoms eventually shade into manic between major depression and hypomania), and symptoms. No “hard and fast” line separates them. Bipolar I Disorder (fluctuations between major Hypomanic episodes are described in terms exactly depression and mania). similar to manic episodes, except they are of shorter We are primarily concerned in this chapter duration and less severe. As the pendulum of mood with medications used to treat Bipolar I Disorder, col- moves further to right toward elevated mood, the loquially known as “manic-depressive illness.” 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. 190 PART TWO Introduction Although so-called mood stabilizers are used to treat As noted, Bipolar I Disorder is predominantly char- Schizoaffective Disorder, Bipolar II Disorder, Border- acterized by symptoms that meet the criteria for line Personality Disorder, and Cyclothymia, these uses major depression and symptoms that meet the cri- are not yet systematic, the literature is inconsistent, teria for mania. The estimated lifetime prevalence and mood stabilization focuses on manic symptoms fluctuates between 0.4 and 1.6% of the adult popu- (Delgado & Gelenberg, 2001). We cover lithium lation (Kessler et al., 1994). In DSM-5, there are and several anticonvulsant medications, some of new categories replacing what were Mood Disor- which have demonstrated efficacy for treating Bipolar ders in DSM-IV. One such category is Bipolar and I Disorder and others that are still under study. We also Related Disorders that includes Bipolar I, Bipolar discuss atypical antipsychotic medications, as well as a II, and Cyclothymia. new, hybrid medication combining olanzapine/ Prevalence estimates are very difficult to come Zyprexa with fluoxetine/Prozac (brand name by, and some practices used to justify them are Symbyax). Because there are so many brand names questionable. In Ohio in 2003, a psychiatrist on a and formulations of lithium (e.g., Lithobid, Eskalith, cable-access news program stated that the incidence Lithonate), we will depart from our generic/Brand of Bipolar I Disorder is significantly higher than name presentation in this case and simply refer to it as currently believed. To support this assertion, he “lithium.” We will do the same when discussing cited some survey research (Hirschfeld et al., valproic acid and use the term Valproate. 2003). He did not say that the survey in question Note that the literature on medications for Bipo- was extrapolating diagnoses from a 10-item ques- lar I Disorder often use “mood stabilizer” as synony- tionnaire (which is not clinically ethical), that the mous with “antimanic.” We use the phrase “mood 10-item questionnaire had only fair validity, and stabilizer.” It is also important to note that the so- that 10 of the 11 authors received substantial finan- called mood-stabilizing medications described in this cial support from pharmaceutical companies. This chapter are increasingly being used in an attempt to was hardly a good citation of a supposedly objec- control aggressive behavior, particularly in children tive, scientific study. Our point is that most viewers and adolescents (Viesselman, 1999). We discuss this may not have even bothered to look up the study use as well as the fact that little research supports this to which the speaker was referring and might practice in the next chapter. believe him simply because he was a psychiatrist. Estimates have sometimes been made for how Review Questions many people are thought to suffer from Bipolar I, II, and Cyclothymia. These estimates are about What is your reaction to the origin of the 4% of the population (Advokat, Comaty, & Julien, phrase “mood stabilizer?” 2014) but that is not an appropriate practice. What qualities make a drug a good mood In preparation for the release of the DSM-5, stabilizer? some advocated that all these disorders should be placed on a continuum called Bipolar Spectrum Disorder (Akiskal & Banazzi, 2006; Ghaemi, Ko, & Goodwin, 2002; Paris, 2009). In DSM-5, Bipolar SECTION TWO: BIPOLAR I DISORDER and Related Disorders were given their own cate- gory but it is NOT a spectrum. The concern with Learning Objectives the spectrum idea was the possibility that clients who showed symptoms of irritation or inattention Be able to understand the challenges in identifying the etiology and proper treatment of Bipolar I Disorder. (especially children and adolescents) would get mis- diagnosed under the bipolar spectrum umbrella Know the spectrum of symptoms as well as the challenge of the specifiers “mixed episode” and “rapid cycling.” with Bipolar I Disorder (Baroni, Lunsford, Lucken- baugh, Toubin, & Leibenluft, 2009; Paris, 2009). 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 EIGHT Mood Stabilizers 191 And it should be added that the DSM-IV Task an integrative perspective, this hypothesis is not Force rejected the idea of childhood Bipolar Disor- terribly useful. It might be just as useful to say der because there was not enough evidence that the disorder “appears karmic.” Some promising (Frances, 2013). Although some researchers (Alloy developments are occurring in molecular psychia- et al., 2012; Walsh, Royal, Bronw, Barrantes-Vidal, try, but more work needs to be done before a & Kwapil, 2012) have explored what they call coherent theory can be articulated (Manji, Moore, a “soft” Bipolar Spectrum, currently Bipolar I, Rajkowska, & Chen, 2000). Despite the ignorance Bipolar II, and Cyclothymia should be conceived about etiology, as with Schizophrenia, the spectrum of as discrete disorders rather than thinking of of symptom presentation in Bipolar I Disorder Cyclothymia or Bipolar II as leading to Bipolar I requires comment. or diagnosing subthreshold symptoms. The mean age of onset for Bipolar I Disorder is Symptoms in Bipolar I Disorder 18 (Weissman, Bruce, Leaf, Florio, & Holzer, 1991). The American Psychiatric Association Bipolar I Disorder is unique in that symptoms (2013) describes Bipolar I Disorder as a long-term manifest heterogeneously, which influences treat- illness with a variable course. The association esti- ment (Pacchiarotti et al., 2013). About half of all mates that 90% of clients who suffer a single manic clients suffering from Bipolar I Disorder have psy- episode repeat the experience. The majority of chotic symptoms and these clients respond less manic episodes (60 to 70%) occur immediately well to some treatments, lithium in particular before or after an episode of major depression (Bowden, 1998). Most clients suffering from (American Psychiatric Association, 2013). Most Bipolar I Disorder return to adequate functioning patients seek treatment for depression and may be between episodes (approximately 80%); however, misdiagnosed with unipolar depression for years many require continued pharmacologic interven- (Angst et al., 2011). There are several specifiers tions to avoid future episodes. As with Schizo- for the disorder (that used to be subtypes in phrenia, clients with Bipolar I Disorder are at DSM-IV ), mixed episode and rapid cycling being a greater risk for suicide: the completion rate is the most difficult to treat. Mixed episode is when 10 times that of the general population (Advokat the person has both symptoms of depression and et al., 2014). mania. Rapid cycling is when the person has Researchers estimate that 35 to 50% of clients four or more episodes (manic or depressive) in a who do stay on medication are likely to suffer 12-month period. In addition, 60% of people relapse despite medication compliance (Advokat et suffering from Bipolar I Disorder have comorbid al., 2014). Many clinicians assume that patients sta- substance use issues and substance use is correlated bilized will continue on the medication indefi- with a greater risk of switching from depressive nitely. There is some evidence in favor of slowly symptoms to manic symptoms (Ostacher et al., titrated withdrawal in patients who have made 2010). therapeutically based life changes and seem able to Scientists do not know what causes Bipolar I manage their illness. We say more about this later Disorder. This is surely dismaying to the clients when we explore the disorder from various who suffer its symptoms, but the truth is, the perspectives. well-intentioned theorists who share a strong med- ical model perspective tend to theorize exclusively Review Questions from this perspective. Although a great deal of attention has been placed on heritability, this Why is treating Bipolar I Disorder so difficult? focus has not provided clues as to the etiology of What specifiers are harder yet to treat effec- Bipolar I Disorder other than giving people the tively and why do you think that is? luxury of speculating that it may be genetic. From 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. 192 PART TWO Introduction SECTION THREE: SOME HISTORY that has been used therapeutically in a number of ON MOOD STABILIZERS ways for almost 200 years. Researchers realized that lithium dissolved kidney stones, so perhaps it would be useful for other disorders related to uric acid. Learning Objectives From a period spanning 1840 to 1870, Alexander Be able to describe some of the accidental events that Ure and Alfred Garrod began experimenting with went into the discovery of lithium. lithium as a treatment for disorders believed related to uric acid (Lenox & Manji, 1998). As Healy (2002) documents, the effects of In the 19th century, a popular theory called uric acid lithium on urates gave rise to an industry in diathesis was a dominant concept in medicine used lithium-laced products. Although many readers to explain the etiology of disorders as diverse as may know that Coca-Cola at one time had coca manic-depressive illness and cardiac problems leaf extract as one of its ingredients, you may be (Healy, 2002). As Barlow and Durand (2002) have surprised to know that 7-Up came on the market noted, “diathesis” means vulnerability (as in the as a lithium-containing beverage. Spring waters diathesis–stress model of psychopathology), in this containing lithium were carried by spas and were case, vulnerability to the effects of the uric acid on supposed to induce a sense of well-being, and lith- one’s system. Uric acid is a breakdown product of ium was even used as a salt substitute for patients urea, which is a compound, found in urine as a with heart problems. As early as 1870, the Danish result of protein metabolism. neurologist Carl Lange (co-creator of the James- In the 19th century, as today, theories followed Lange theory of emotions) found that lithium had the technologies available to test them. The ability therapeutic effects in clients with manic-depressive to peer inside neurons is followed by theories of illness. In the United States, William Hammond mental disorders that hypothesize intraneuronal gave lithium to patients with mood disorders and (and interneuronal) causes, as you saw in our also reported positive results (Healy, 2002). One Chapter Five discussion of depression (remember problem with lithium, however, is that in large the molecular/cellular theory of depression?). In enough doses it can be toxic, and there were the 19th century, chemical analysis was the newest some fatalities from these enthusiastic additive uses technology of that time, so researchers used it to of the substance. This, coupled with the decline of investigate substances eliminated from the body the uric acid diathesis hypothesis of illness, contrib- and then proposed theories about disorders, uted to the FDA removing lithium from the market based on the analysis. Although the uric acid in 1949. Ironically, this same year a little-known diathesis theories are now recognized as no more psychiatrist from Australia was about to put lithium accurate than the chemical imbalance theories of “back on the map.” depression, they did provide a starting point for research that led to lithium being used for Bipolar Developments Down Under I Disorder. John Cade was a psychiatrist and state hospital Uric acid was also found to be a major constitu- superintendent in Australia in the mid 20th century. ent in kidney stones and gout. Gout is a painful Under the influence of the uric acid diathesis the- inflammation of the joints, caused by uric acid in ory, Cade hypothesized that a toxin that entered salt form settling in joints. In the 19th century, gout the brain caused mania. He further asserted that was also linked to disturbances in mood (although this toxin could be detected in urine. He proposed these surely could have been side effects of the injecting uric acid from manic patients into guinea unpleasant experience of having gout). In 1817, a pigs, thinking that if the hypothetical toxin were new element called lithium had been discovered. active, it would induce manic activity in the guinea Lithium is a light, positively charged metal ion pigs. Alas, uric acid is highly toxic and the first 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 EIGHT Mood Stabilizers 193 guinea pigs died. He then decided to dissolve the but when monitored and given in appropriate acid by mixing it with a metal to form a soluble salt. doses, the cardiac side effects of lithium are typi- After failing with a number of metals, he found cally minor (Tilkian, Schroeder, Kao, & Hultgren, lithium ideal for his mixture. He then injected the 1976). As we outline later, lithium therapy must dissolved mixture of uric acid and lithium into the be closely monitored, because the therapeutic dose guinea pigs, and they responded not with mania but is very close to the toxic dose. The only FDA- lethargy. Cade thought the lethargy was a calming approved use of lithium is for mood stabilization. effect and eventually tried injecting just lithium into the guinea pigs. It had the same effect (in actuality, the lithium did not calm the guinea pigs, it just Review Question made them sick). At any rate, although this was not at all what he had expected to find, Cade What are some of the accidental discoveries (1949) concluded that lithium might have some that went into figuring out lithium could be effects on mood (calming what he called “psychotic used to treat Bipolar I Disorder? excitement”), and he proposed to test it in humans, including himself (Snyder, 1996). Although Cade had some success using lithium in manic patients, SECTION FOUR: LITHIUM: THE several of his patients died from its toxicity (Healy, PROTOTYPICAL MOOD STABILIZER 2002). Although some give Cade all the credit for dis- covering lithium (Snyder, 1996), others (Healy, Learning Objectives 2002) cite the important contributions of Morgens Be able to give an overview of at least four mechan- Schou, a Danish researcher. Schou (1978) did the isms of action of lithium and why we think they may first randomized, controlled trials that demonstrated help in Bipolar I Disorder. the efficacy of lithium. Although Cade had some Be able to describe the categories of side effects from success, it was anecdotal and not based on standard lithium. trials. Schou’s research confirmed the usefulness of Know the profile of who is a good candidate for the compound and led to standards for safe dosage lithium. levels. Note that there is still no theoretical basis for lithium’s use. As Snyder (1996) concludes, “One of the fascinations of the discovery process is that we As noted, lithium is a naturally occurring, posi- often find the right answer by looking in the wrong tively charged alkali metal ion. Johan August Arf- place” (p. 119). vedson in Stockholm, Sweden, discovered it in As noted, lithium was taken off the market in 1817. Its name derives from the Greek lithos, 1949 (the same year it appeared to have efficacy meaning “stone” because Arfvedson discovered it for manic-depressive illness) and was not reap- in a mineral source. It can be mixed with magne- proved by the FDA for psychiatric use until sium and aluminum to form metal alloys, is used 1970. Some think part of the reason for this time in some glasses and batteries, and of course has use lag was that because lithium is a naturally occur- in psychopharmacology. It has been assumed that ring element, no pharmaceutical company could lithium has good efficacy in treating acute mania get a patent on it, thus limiting its profitability. as well as being a prophylactic for both manic and The toxicity of lithium was surely another reason depressive episodes (American Psychiatric Associa- for the caution in approval. The early deaths tion, 2000a) and was the drug of first choice for related to lithium were all caused by lithium- Bipolar I Disorder. The problem is that in “real induced cardiac problems. Researchers now life,” many patients stop taking it because of its dif- think these cases were all cases of lithium toxicity, ficult side effect profile. Right now, anticonvulsants 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. 194 PART TWO Introduction and atypical antipsychotics are more often the first TABLE 8.1 Examples of Lithium Formulations drugs prescribed because clients do not want to be bothered with side effects and the blood testing Generic Brand Names Formulation necessary when taking lithium. Many still feel Lithium citrate Cibalith-S Syrup that lithium has the best efficacy in studies compared to other drugs and that it enhances the effects of Lithium carbonate Eskalith Capsule antidepressants (Grof & Muller-Oerlinghausen, 2009). As usual, though, there are disagreements in Eskalith-CR Scored tablet the literature and the differences between what works in short-term studies versus what is necessary Lithobid Tablet managing a chronic disorder are different things Lithotabs Tablet (Post, 2010). The evidence for lithium to treat bipolar depression is weaker than for its effectiveness Lithane Gelatin capsule in bipolar mania. Lithium does seem (when clients © Cengage Learning® adhere to prescription) to have strong efficacy in maintenance of euthymia and prevention of relapse benzodiazepines (Advokat et al., 2014). Once a cli- (Malhi, Tanious, Das, Coulston, & Berk, 2013). ent starts to show a response to lithium, symptoms Throughout the mid to late 20th century we usually diminish quickly. If lithium is discontinued had consistent support for the idea that long- abruptly during the manic phase of the illness, term lithium therapy correlated with decreased relapse may occur rapidly (Perry, Alexander, & suicide rates in clients suffering from Bipolar I Liskow, 2006). Lithium is not metabolized and is Disorder (Goodwin & Ghaemi, 1999). Lithium excreted unchanged by the kidneys which puts a may also have neuroprotective properties, strain on them. Thus, long-term lithium users which would mean that Bipolar I Disorder is should be screened regularly for markers indicating progressive and/or degenerative and lithium pro- kidney damage (Rybakowski et al., 2012). tects neurons from the progression of the disor- As with all mental disorders, we do not know der. As with most hypotheses, more work needs what causes Bipolar I Disorder. This makes finding to be done to confirm this one (Manji et al., an effective intervention challenging and severe 2000). Lithium is least effective in clients suffer- mental disorders like BPI seem to be rooted in ing from mixed episodes or rapid cycling of the brain, which makes things even more compli- mood symptoms (Bowden, 1995). Lithium is typ- cated as we are just beginning to realize how little ically available in capsules, tablets, slow-release we know about the brain. In placebo-controlled tablets, and as lithium citrate syrup (Keck & studies, approximately 60 to 80% of clients suffering McElroy, 2002). Common lithium formulations from mania show some level of response to lithium are listed in Table 8.1. over placebo. Some researchers (Grof & Alda, 2001; Peak plasma levels for lithium are reached by Grof, Alda, Grof, Fox, & Cameron, 1993) chal- about three hours but lithium is not fat soluble lenge this estimate and believe that the response and does not cross the blood–brain barrier easily. rate is closer to 50%. Chen, Mehta, Aparasu, Because of this, the therapeutic dose can be close Patel, and Ochoa-Perez (2014) concluded that to the toxic dose which as you can imagine is monotherapy with atypical antipsychotics was problematic. Clients show an initial response within more effective and safer than monotherapy with one week to one month of beginning lithium ther- mood stabilizers for adolescents. Because in many apy. Because of this time lag and because clients cases people are treated with multiple medications, suffering from manic symptoms may endanger it is harder to specify response rates to one. Grof themselves or others, additional medications (2006) has summarized research into a profile of may be used, including typical antipsychotics and patients who are good lithium responders. So, we 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 EIGHT Mood Stabilizers 195 might ask, what are the “symptoms” of a good lith- that question, we begin by discussing the mechanisms ium response? According to Grof, they include: of action of lithium. Complete remission between episodes Mechanisms of Action Depressive symptoms are more vegetative in The pharmacology of lithium is incredibly complex nature (similar to what we said about depression and a matter of ongoing speculation. Lithium affects in Chapter 5) different parts of the brain differently at different The person does not meet criteria for rapid times when different doses are used. Lithium’s cycling or mixed episode specifiers effects extend to multiple neurotransmitters and No significant psychiatric comorbidity (but second-messenger systems. remember in some studies up to 60% of people As all researchers point out, we are still uncertain of with BPI meet criteria for substance use disorders) the key factors in lithium’s effectiveness. Table 8.2 Episodic course in another family member outlines the mechanisms of action we know lithium Another way to look at this is that combination exerts. Note that part of the complexity of lithium is therapy has become standard practice but even due to the fact that it can affect the brain differently in there it depends on the presentation of symptoms. different regions (e.g., increasing neurotransmitter For example, lithium seems most effective for release in some areas and decreasing release of the enhancing the effects of antidepressants for refrac- same neurotransmitter in other areas). These mechan- tory patients. Anticonvulsants plus lithium seem to isms are summarized from Malhi et al. (2013); Perry provide better protection against relapse than just et al. (2006); and Schatzberg, Cole, and DeBattista lithium (Leng et al., 2008). On the other hand, (1997). combination therapies that we seemed to think The best-studied effects of lithium are on had efficacy in the first edition of this book, turned serotonin, and these effects also demonstrate the com- out not to. The most common practice was adding plexity of lithium’s pharmacodynamics. After short- antidepressants to mood stabilizers, which Sachs term use (one to two weeks), lithium appears to et al. (2007) concluded did not improve response. increase serotonin synthesis by increasing tryptophan Lithium treatment cannot occur until clients have reuptake in synapses. After two to three weeks, it several lab tests done, including checking sodium, appears to enhance release of 5-HT from neurons in calcium, and phosphorous levels, and an electrocar- the parietal cortex and the hippocampus. Long-term diogram, urinalysis, thyroid battery, and complete taking of lithium seems to cause downregulation in 5- blood cell count. HT1 and 5-HT2 receptors. Again, how these effects Because the average duration of a manic episode may relate to mood is currently unknown. is three months, plasma levels of lithium effective Lithium’s effects on norepinephrine (NE) are for the client should be maintained for three to six equally curious. Lithium appears to increase the months afterward. If lithium is to be discontinued, rate of norepinephrine synthesis in some parts of Perry et al. (2006) recommend that the daily dosage the brain. It decreases excretion of norepinephrine be tapered by 25% each day over a period of four metabolites in manic patients but increases excretion weeks. About half of patients stabilized successfully of norepinephrine metabolites in depressed patients. on lithium and then switched to placebo relapse Lithium appears to block postsynaptic DA receptors, within six months. There are stories of patients which seems to partly explain the controlling effects relapsing in a few days, but these are not from con- on mania and psychosis. There appears to be evi- trolled studies and are rare. dence that lithium affects the G-proteins in Unlike antidepressants, there are more often signif- second-messenger systems. Apparently it inhibits icant statistical differences between lithium and pla- some enzymes, in particular second-messenger sys- cebo groups in participants with Bipolar I Disorder. tems, which in turn is believed to bring about Clearly something is happening, but what? To address some of the therapeutic effects. 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. 196 PART TWO Introduction TABLE 8.2 Mechanisms of Action of Lithium Neurotransmitter System Effects Serotonin Increase in tryptophan (precursor) uptake after short- and long-term treatment. General increases in serotonin levels. Increased release of serotonin in the hippocam- pus, hypothalamus, and parietal cortex. Serotonin receptor decreases in hippocampus. Long-term administration causes downregulation of 5-HT1 and 5-HT2 receptors. Dopamine Long-term administration diminishes neostriatal dopamine activity. May block the effects of highly sensitive DA receptors, thus decreasing the behaviors associated with DA stimulation. Norepinephrine Increases rate of synthesis of NE in some parts of the brain but decreases the synthesis in other parts. Decreases the excretion of NE metabolites in manic patients and increases the excretion of NE metabolites in depressed patients. Second-messenger systems Lithium appears to reduce the activity of second-messenger systems in undetermined ways. Ionic effects Lithium, being a positively charged metal ion, may have stabilizing effects on neurons in the CNS. Inhibiting Intracellular Inhibition of glycogen synthase kinase-3 (GSK-3) increases Beta-catenin that stimulates Enzymes axon growth and cell survival. Neuroprotection Antioxidant properties may protect brain from oxidative stress. © 2015 Cengage Learning® We know that in BPI, there are gray matter only seen the proverbial “tip of the iceberg” in deficits, meaning, that compared to unaffected indi- terms of lithium’s mechanisms of action, and contin- viduals and those who had brain scans after lithium ued research will likely yield a deeper understanding treatment, people suffering from BPI seem to have of its effects on brain chemistry. reduced volume in the subgenual and anterior cin- gulate cortex as well as the prefrontal cortex. Some Theories of Lithium Action of these reductions are hypothesized to be the result The short answer to the question “How does lith- of excitotoxicity caused by glutamate-induced ium work?” is “We don’t know.” Because stress. In patients (some but not all of course) who researchers do not really know what causes have responded to lithium treatment, these gray Bipolar I Disorder, it is hard to draw definitive matter reductions decrease or vanish in subsequent conclusions as to how lithium corrects the disor- brain scans positing a neuroprotective mechanism der in people who respond to it as a treatment. in lithium (Malhi et al., 2013). Next, we briefly outline some medical model If even after reviewing our brief description of theories that have implications for psychosocial lithium’s mechanisms of action you are confused, interventions as well. you are not alone. Scientists do have molecular clues as to lithium’s pharmacodynamics, but these clues do not help explain how it alters mood. From Lithium and Neurotransmission an integrative perspective, this is likely because mood The Amine Theory Revisited cannot be explained in terms of brain chemistry In Chapter Five, we discussed the amine theory of alone. In fairness though, researchers have likely depression, which in essence proposed that people 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 EIGHT Mood Stabilizers 197 whose nervous systems did not produce enough and all may not be necessary to bring symptom amines (specifically norepinephrine) become relief in BPI. Until we know more about the etiol- depressed. From here, it was a simple leap to pro- ogy of BPI though, we don’t know which equation pose that some people’s nervous systems produce variables we can dispense with. amines erratically, sometimes producing too many, and at other times producing too few. When the Dopamine nervous system of such afflicted people produces Dopamine (DA) is an excitatory neurotransmitter too many amines, the result is manic mood. that many researchers believe is an important variable When the person’s nervous system produces too in the equation in the symptoms of BPI and few amines, the result is depression. This appeared lithium’s action. During mania, DA metabolites are to have limited support in that lithium is correlated increased in some but not all patients which may with decreased norepinephrine metabolites in point to an increase in actual DA (Cousin, Butts, manic patients and increased NE metabolites in & Young, 2010). If DA transmission is elevated dur- depressed patients. These data led researchers to ing mania then it may prompt a balancing (homeo- conclude that lithium helped the body achieve static) mechanism that could then cause depression. some innate homeostasis (dare we say, “chemical Animal models of lithium action show extracellular imbalance?”) that had been lacking. Obviously, in DA to decrease after the introduction of lithium. light of how complex lithium’s effects are, this The postsynaptic actions of DA are mediated by chemical imbalance theory also turns out to be as G-protein receptors, which then stimulate second oversimplistic and inadequate as is the chemical messenger systems like adenyl cyclase (AC) and imbalance theory of depression. cyclic adenosine monophosphate (cAMP). Research suggests that lithium also alters the function of these Lithium’s Ionic Impact on units in ways that may be neuroprotective. Neurotransmitter systems That lithium is a positively charged metal ion may Glutamate and NMDA Receptors account for lithium’s effects on the nervous system. Glutamate (Glu) like DA is an excitatory neuro- As Preston, O’Neal, and Talaga (2002) note, “Since transmitter. Michael, Erfurth, Ohrmann (2003) neurotransmitter production, release, and reuptake first hypothesized that glutamate was elevated in rely on various ions (sodium, calcium, potassium, manic episodes. N-methyl-D-aspartate (NMDA) and magnesium), lithium’s ionic properties may receptors, among other things, control many aspects affect neurotransmission-mediated depression and of memory and plasticity. They also open ion chan- mania” (p. 187). This hypothesis is certainly plausi- nels that can increase sodium and calcium, posi- ble. As you saw in Chapter Two, all neurons have tively charged ions that would increase cell firing. ion channels that allow the passage of positively or With chronic lithium administration, lithium binds negatively charged particles into the cell. We noted to NMDA receptors and this causes downregula- that an influx of positively charged ions (such as tion of the NMDA receptors and enhanced Glu sodium) tends to excite cells and an influx of nega- reuptake (Malhi et al., 2013). tively charged ions (such as chloride) tends to inhibit or hyperpolarize cells. We will now cover hypothesized mechanisms of action for lithium GABA using an algebra equation metaphor. Both the eti- GABA is an inhibitory neurotransmitter that plays ology of BPI and the actions of lithium involve crucial roles in modulating Glu and DA. Here multiple (maybe dozens) variables that could be again, we see the complexity of trying to under- said to resemble an algebra equation with many stand the relationship between neurotransmitter unknown variables. Each of these hypothesized families. Patients with BPI are thought to have mechanisms may play a part of the action of lithium diminished GABA transmission that then leads to 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. 198 PART TWO Introduction increases in excitatory transmission via DA and Glu. human beings (Lenox & Manji, 1998). Although This leads to excitotoxicity that in turn causes cell studies with humans are hampered by several ethi- loss and perhaps accounts for the decreased brain cal limits that do not constrain animal models, it structure volume in patients with BPI. Lithium appears that lithium significantly slows and length- increases the level of GABA in the plasma and spi- ens the circadian cycle. More recently, McCarthy nal fluid of people and so supposedly it also et al. (2013) tied BPI disorder to those genes tied to increases it in the central nervous system. the circadian cycle. Their research conclusions sug- gest that lithium enhanced the resynchronization of Lithium’s Effect on Second-Messenger circadian rhythms and that may be one therapeutic Systems mechanism in the equation of symptom relief. In the late 1980s and early 1990s, researchers pro- posed that intraneuronal effects caused lithium’s Side Effects of Lithium therapeutic effects. They specified second- Approximately three-fourths of clients on lithium messenger systems as a primary site where lithium experience side effects (American Psychiatric Asso- exerted a powerful influence. In this theory, the ciation, 2000b). The side effects are a primary rea- lithium acts to modulate these systems, in some son for clients to stop taking the drug (Atack, 2000; cases slowing them down and in others speeding Advokat et al., 2014). One problem is that the ther- them up (Avissar & Schreiber, 1989; Malhi et al., apeutic dosage is often close to the toxic dosage, so 2013; Weber, Saklad, & Kastenholz, 1992). Recall the drug requires regular blood monitoring in cli- from Chapter Two that second-messenger systems ents. The side effects of lithium are summarized in may play a role in neuronal excitation and subse- Table 8.3 and then described more fully in the text. quent firing. In this theory, the slowing of the The types and degrees of side effects clients will second-messenger systems may decrease cell firing suffer are difficult to estimate. The literature on and (theoretically) decrease manic symptoms. It side effects has always given broad ranges of the now appears these may be only one of many percentage of patients complaining of adverse effects that ultimately translate into therapeutic effects (35 to 93% according to Lenox and Manji, gains. Some of the second-messenger systems are 1998)—so broad as to be not much help. Price and responsible for the production of brain-derived Heninger (1994) noted that the side effects increase neurotrophic factor (BDNF) that (recall from as the serum levels of the drug increase. It is impor- Chapter Five) acts as a brain cell nutrient repairing tant to note that clients will have different numbers cells and stimulating neurogenesis. Lithium seems and degrees of side effects, and that lithium’s diffi- to enhance the production of BDNF in parts of cult side effect profile is a main reason that contin- the brain. ued research on different mood stabilizers is important. When the percentage is generally Lithium and Circadian Rhythms known, we have also listed in parentheses the pro- As early as 1990, researchers have sought to explore portion of clients thought to suffer from a given the connection between Bipolar I Disorder and side effect. Data for Table 8.3 are drawn from sleep–wake cycles that are part of our circadian Lenox and Manji (1998); Perry et al. (2006); and rhythms (biologic cycles within the course of a Schatzberg et al. (1997). day) (Goodwin & Jamison, 1990). This theory reflects the psychosocial intervention of optimizing CNS Side Effects of Lithium sleep and setting regular patterns of sleep and wake- The cognitive side effects of lithium may be the fulness with clients suffering from Bipolar I Disor- most troubling for clients but remain the least stud- der. The circadian rhythm hypothesis of lithium’s ied (Jamison & Akiskal, 1983; Lenox & Manji, action derives from the fact that lithium slows the 1998; Shaw, 1986). From the psychological per- circadian rhythm in species ranging from plants to spective, clients say lithium decreases creativity 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 EIGHT Mood Stabilizers 199 TABLE 8.3 Side Effects of Lithium Type of Effect Description CNS effects Contradictory evidence of deleterious cognitive effects on concentration, memory, and creativity Seizures can occur as a result of lithium toxicity Neuromuscular Tremors at rest or although moving (4%–65%) Muscle weakness (40% in short-term treatment) Gastrointestinal Chronic nausea, diarrhea, occasional blood in stool Endocrine Weight gain (11%–64%), Hypothyroidism (approx. 4%), Goiter (approx. 6%), Elevated thyroid-stimulating hormone (30%) Renal Polyuria/polydipsia (20%) Dermatologic Acne and rashes, Aggravation of psoriasis, Alopecia Hematologic Increase in white blood cells (75%–100%) Teratogenic Increased risk of Epstein’s anomaly, a congenital heart defect characterized by displace- ment of the tricuspid valve Sexual Decreased libido in males and females, erectile dysfunction in males © Cengage Learning® and concentration and increases forgetfulness. caffeine can worsen the tremor. Although the tremor Schatzberg et al. (1997) have noted that forgetful- is reversible with discontinuation of the medication, it ness is one of the most common reasons given by may also be controlled by lowering the lithium dosage clients who stop taking lithium. The few existing or by administering a beta-blocking agent (such as that studies have produced conflicting data. Judd, described in Chapter Six). Although the source of Squire, Butters, Salmon, and Paller (1987) reported lithium-induced tremor is uncertain, it is not related slowed rate of central information processing with to the extrapyramidal side effects caused by neurolep- short-term use of lithium. Some of these effects tics described in Chapter Seven. Several studies have seem to diminish with long-term use, suggesting shown that medications used for EPS are ineffective there is some accommodation to the effects. More with lithium-induced tremor. General muscle weak- research on this problem is warranted, and clinicians ness is also a common neuromuscular side effect of should monitor cognitive functioning in clients lithium and is reported in about 70% of clients within receiving lithium. Cognitive impairment can also the first two weeks of taking lithium. Again, this side be a sign of lithium toxicity. effect is dose related and appears to resolve on its own after the first two or three weeks of lithium use. Neuromuscular Side Effects of Lithium The most reported neuromuscular side effect of lith- Gastrointestinal Side Effects of Lithium ium is tremor. The tremor can occur while the client is Gastrointestinal (GI) side effects can range from at rest or moving. The incidence of tremor (like most mild to severe, with milder effects that include estimates of side effects) is quite broad (4 to 65%) but bloating and slight abdominal pain and severe the symptom is directly correlated with the client’s effects that include nausea and vomiting. It is lithium level. Emotional stress and stimulants such as important for clinicians to monitor these side effects 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. 200 PART TWO Introduction closely, because they are also signs of lithium toxic- periods of lithium toxicity are at greater risk for this ity. Perry et al. (2006) noted that GI side effects disorder. These side effects have led to the recom- frequently subside on their own and can be dimin- mendation that clients on lithium have kidney ished if the medication is taken with food. Some- function checked every 6 to 12 months (Schatzberg times, the daily required dosage can be divided into et al., 1997). more numerous, smaller portions. Although there are currently sustained-release formulations of lith- Dermatologic Side Effects of Lithium ium, studies indicate no real benefits in terms of side The dermatologic side effects of lithium include effect profile. various rashes and outbreaks on the skin, aggrava- tion of existing dermatologic conditions, and hair Endocrine Side Effects of Lithium loss (alopecia). Cases of rashes, acne, or other out- The most problematic endocrine-related side effect breaks on the skin may resolve by themselves. Low- of lithium is weight gain. It has been clearly tied to ering the dosage frequently relieves them. Few lithium use and is another of the more common studies h