Antipsychotic Medications: Chapter 7 PDF

C H A P T E R S E V E N Antipsychotic Medications The Evolution of Treatment Many readers may begin this chapter with some being treated. The video progresses, showing the familiari...

C H A P T E R S E V E N Antipsychotic Medications The Evolution of Treatment Many readers may begin this chapter with some being treated. The video progresses, showing the familiarity with antipsychotic medications. Others young man at monthly intervals as he is slowly may think antipsychotic medications or the weaned off the medications causing the side effects, research related to them has not affected their and gradually titrated onto a new medication lives. These latter readers may be wrong. Have (clozapine). With each passing month, we see that you ever taken a prescription antihistamine such the young man’s psychotic symptoms remain under as Seldane or Allegra? Perhaps got over motion control but that he is gradually regaining control of sickness with a compound that included pro- his body. In the final video frame, we see the same methazine? If so, your life has been affected by young man enjoying a game of basketball and research into antipsychotics. As with so many apparently having no problems with movement or other areas of research in psychotropic medica- symptoms of psychosis. tion, antipsychotics and theories about their use This was one of the first videos promoting what have been developed through combined scientific we describe later as an atypical antipsychotic, and at effort, clinical research, market-driven agendas, the time of their development most of us believed and serendipity. Let’s look at some history to that clozapine and drugs modeled after its molecular introduce this topic. The primary source for the structure launched another revolution in psycho- following is Healy (2002). pharmacology. It was hoped that (as was hoped in the SSRI revolution in antidepressants) the new THE CURRENT IMPACT OF antipsychotics would change the way psychotic dis- orders are treated as well as the quality of life that ANTIPSYCHOTICS patients can expect during treatment. As we will In a video designed for psychiatrists (Novartis Phar- see, although newer agents do work better for maceuticals, 1998), a young man suffering from some but not all people with schizophrenia, the treatment-resistant schizophrenia is shown in an newer agents have problematic side effects similar inpatient setting. Although his psychotic symptoms in impact (if different in quality) as the older agents. are temporarily under control, he is so incapacitated Also, the claims that newer medications worked by medication side effects that he can barely walk better than the older ones now seem to be untrue across a small room. His movements are jerky con- ( Jones et al., 2006; Lieberman et al., 2005). tractions of muscle groups that he can hardly This chapter is divided into seven sections. The control. Anyone who has treated clients taking first is an overview of schizophrenia and the spec- conventional antipsychotic medications knows trum of symptoms being treated. The second that this young man is living a worst-case scenario focuses on theories of neuroleptic antipsychotic in which the treatment is worse than the disorder action. Section Three is an overview of the side 150 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 SEVEN Antipsychotic Medications 151 effects of first generation, neuroleptic medications. (although nothing as simple as dopamine imbalance Section Four is an introduction to the first atypical as was believed in the mid to late 20th century). antipsychotic, clozapine/Clozaril. Section Five Prevalence among adults is thought to be between covers the rest of the drugs modeled on clozapine 1 and 1.5% of the adult population (American Psy- called serotonin-dopamine antagonists. Section chiatric Association, 2013). Keshavan (2013) has Six looks at newer compounds and theories of advocated eliminating the name “Schizophrenia” how to create more effective antipsychotics. The because it conveys an inaccurate characterization final section looks at psychological, cultural, and of the symptoms, has acquired a negative connota- social issues relevant to antipsychotic medications. tion (like “lunacy”), and belies what we are learning neurobiologically about the disorder. Keshavan et al. (2013) have suggested an acronym “CON- SECTION ONE: SCHIZOPHRENIA CORD,” which stands for “youth onset conative, cognitive and reality distortion” (p. 1). As Keshavan Learning Objectives notes, we do not take lightly renaming a disorder but the label of “schizophrenia” seems to be Have a sense of the complexity of theories of etiology obsolete. for schizophrenia. One of the most distressing aspects of schizo- Be able to discuss why the name “schizophrenia” is not terribly useful. phrenia is that it seems to be correlated with pre- mature death. Even more disturbing is that we still Understand positive symptoms, primary negative symptoms and secondary negative symptoms. have to discern if this is related to the disorder, the medications people with the disorder take, or both. Joukamaa and colleagues (2006) did a 17-year fol- Schizophrenia “… definitely involves genetic fac- low up of 99 people with schizophrenia. Of the 99, tors the precise genes and gene-environment inter- 39 died in that 17 years. Adjusted for age and sex actions are yet to be clarified” (Keshavan, Tandon, and other diseases, the risk for premature death was & Nasrallah, 2013, p. 4). As Stober et al. (2009) significantly higher than expected. The deaths also concluded, “the phenotypic complexity, together increased as the number of neuroleptics taken with the multifarious nature of the ‘group’ of increased. Even though we have agents to treat ‘schizophrenic psychoses’ limits our ability to form the symptoms of schizophrenia, as noted above, a simple and logical biologically based hypothesis of they do not really differ much from one another the disease group” (p. 129). Schizophrenia shares in general effectiveness and what is needed is that many heritable factors with Bipolar I disorder, sug- we understand the mechanisms underlying the ill- gesting there may be an underlying genetic basis for ness and its progression. Until we can accomplish both disorders that runs on a continuum. At the this, we will remain stuck in symptom management more severe end of the continuum, the person is (Kane & Correll, 2010). afflicted with schizophrenia; at the less severe end (if it is fair to use that phrase in regard to any of these The Spectrum of Symptoms disorders), the person is afflicted with Bipolar I Dis- in Schizophrenia order (McIntosh et al., 2006). Ultimately, though, In DSM-5 (APA, 2013), the category Schizophrenia schizophrenia is a disorder with a heterogeneous and Other Psychotic Disorders of DSM-IV has been presentation involving multiple genes that may changed to Schizophrenia Spectrum and Other each have relatively small effects. Etiological factors Psychotic Disorders. Many aspects of the DSM-5 also include differences in brain structures (Hartberg were designed to reflect the International Classifi- et al., 2011), white matter or the glial cells in the cation of Mental and Behavioural Disorders (ICD- brain (Frances, 2013), and neurochemical variables 10) (WHO, 1992), which includes Schizotypal 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. 152 PART TWO Introduction Personality Disorder under the Schizophrenia head- The second period begins in the early 1960s ing. So in DSM-5, the spectrum of disorders also with the emphasis (begun in the Kennedy adminis- contains a spectrum of symptoms. The spectrum of tration) of community care versus hospital care. At symptoms in schizophrenia includes both positive this time, the National Institute of Mental Health and negative symptoms. This concept derives was labeling antipsychotics “antischizophrenic.” from the work of the 19th-century neurologist At this time, psychological explanations for mental John Hughlings Jackson. Positive symptoms of disorders were dropped in favor of medical model schizophrenia are things the client experiences theories. Some writers at the time (Swazy, 1974) but likely should not be experiencing, such as hal- even posited that chlorpromazine was a “magic lucinations, illusions, delusions, and paranoia. bullet” for schizophrenia (which it never was). Clients with positive symptoms usually lack insight This second period ends in the 1980s with the dis- into the sense outsiders have that these experiences appearance of such overly optimistic views. By the are not real or normal and frequently cannot distin- 1970s, clinicians accepted that neuroleptics could guish between them and the consensual reality produce “alarming side effects, non-profound ben- shared by most others. efits in most cases, and no benefit at all in many” Negative symptoms of schizophrenia are defi- (Gelman, 1999, p. 7). cits in the client’s functioning expressed as things like The third period, encompassing the 1980s and anhedonia (lack of pleasure in life), isolation, with- early 1990s, found many clinicians still clinging to drawal, flat or restricted affect, and reduced motiva- the vague medical model notion of a chemical tion. These negative symptoms severely affect quality imbalance as causing schizophrenia despite the the- of life for afflicted clients and can be exacerbated by ory being increasingly falsified. Although research- certain antipsychotic medications clients are given to ers and clinicians began to understand schizophrenia control the positive symptoms. In addition to the as a complex, overdetermined disorder, many psy- positive and negative symptoms, clients suffering chiatrists continued to follow the chemical imbal- from schizophrenia experience conceptual disorgani- ance theory (old habits die hard and it is easier to zation, which used to be called “thought disorder.” feign certainty than to live in ambiguity). Research This disorganization can range from concrete thinking during this period birthed the atypical antipsycho- to severe loose associations and word salad. tics, and for many psychiatrists these drugs seemed These symptoms may also severely reduce clients’ to continue to support the chemical imbalance the- quality of life (Thaker & Tamminga, 2001). From ory, although they operate very differently from the an integrative perspective, all these symptoms need neuroleptics that actually spawned the theory. Neu- to be addressed. Although pharmacological inter- roleptics block dopamine-2 (D2) receptors whereas ventions are the first line of treatment for schizo- the atypicals block mostly serotonin receptors and phrenia, it is also important to include psychosocial some D2 receptors but not as many as neuroleptics. and educational components (American Psychiatric That these drugs that massively block serotonin Association, 2000a). receptors work as well as neuroleptics that block Gelman (1999) divides the history of medicating D2 receptors calls into question how schizophrenia psychotic disorders into four periods. The first could possibly be just a dopamine imbalance. period encompasses the 1950s and 1960s and The fourth and current period began in the mid- began with the appearance of chlorpromazine 1990s and continues to the present. This period is (Thorazine). In this period, the mechanisms of marked by new imaging technology that allows action for chlorpromazine were not known, and neurologists and psychopharmacologists to more although many people believed this drug would closely examine the brain and the effects of medi- usher in an age of deinstitutionalization, others felt cations on the brain. During this period, researchers it would likely just make hospital wards more will likely continue to construct newer theories to manageable. account for the action of antipsychotic medications. 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 SEVEN Antipsychotic Medications 153 Review Questions impact on the field of psychiatry until the 1970s. The hypothesis proposed that schizophrenia was caused What are some of the variables currently by an undefined problem in dopamine transmission. considered as important to the etiology of The hypothesis grew out of the realization that schizophrenia? chlorpromazine/Thorazine and haloperidol/Haldol Why is the label “schizophrenia” inaccurate both seemed to interrupt dopamine transmission and what could replace it? and decrease the symptoms of schizophrenia. Describe positive symptoms, primary negative Equally, abuse of amphetamine drugs that stimulate symptoms, and secondary negative dopamine can cause symptoms indistinguishable symptoms. from schizophrenia in some but not all people. As you may recall from Chapter Five, this is similar to the amine hypothesis of depression. It posits a simple (too simple) cause-and-effect relationship SECTION TWO: THEORIES OF from observations of medical trials. As in other NEUROLEPTIC ACTION FROM THE cases, though, the reality is far more complex, and MEDICAL MODEL PERSPECTIVE emotional defense of the simple dopamine hypothesis today carries the same authority as emotional procla- mations espoused by the Flat Earth Society. Learning Objectives So how was the dopamine hypothesis devel- Understand the dopamine hypothesis of schizophrenia oped, and what relevance has it for mental health and how it has been falsified. clinicians? Since the early administration of chlor- Be able to describe the primary dopamine tracts in the promazine/Thorazine, researchers had noted that brain and how neuroleptic medications are thought to the drug caused symptoms similar to those in Par- work. kinson’s disease (so named for James Parkinson, Know the four classes of extrapyramidal side effects who outlined the symptoms in 1812). Carlsson (EPS). and Lindqvist (1963) proposed the first variation Know two classes of medications regularly used to on the dopamine hypothesis, but remember that treat EPS. at the time people knew little about neurotransmit- ters and nothing at all about neurotransmitter receptors. Arvid Carlsson discovered dopamine in In this section, we outline the mechanism of action in the central nervous system, where, researchers typical antipsychotics (neuroleptics), detail their com- learned, dopamine was also a precursor to norepi- mon side effects, and discuss how to deal with side nephrine. Studies with reserpine/Serpalan demon- effects. It is interesting that neuroleptics, and chlor- strated that it depleted norepinephrine and promazine/Thorazine in particular, were widely used serotonin from the brain, but when these neuro- before their mechanisms of action were isolated. As transmitters were replaced they did not counter you are now aware, this is not unusual in the history the effects of the reserpine/Serpalan. Carlsson and of psychopharmacology, and the neuroleptics were his colleagues, hot off their discovery that dopamine being used on a global scale before their mechanisms was also present in the brain, assumed that dopa- of action were identified. mine too was depleted by reserpine and discovered that giving research animals a precursor for dopa- The Dopamine Hypothesis mine (levodopa/Carbidopa) did in fact reverse the of Schizophrenia effects of reserpine/Serpalan. Thus was born the The dopamine hypothesis of schizophrenia first variation of the dopamine hypothesis—that (the first “chemical imbalance” theory for the disor- psychoses were somehow related to deficiencies in der) actually was formulated in the 1960s but had no dopamine. 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. 154 PART TWO Introduction The first response to this theory was that it did the drugs act as antagonists, meaning they block not make sense, because chlorpromazine/Thorazine the receptor but exert no effect. They merely did not empty the presynaptic neuron of dopamine block dopamine molecules from binding. The dopa- (recall that researchers had not yet learned mine molecules would exert an effect if they could about receptors). Carlsson and Lindqvist (1963) bind, but they are prevented from doing so as long as demonstrated that chlorpromazine/Thorazine and the person is taking a neuroleptic medication. The haloperidol/Haldol acted on the postsynaptic neu- dopamine hypothesis was a mainstay for understand- rons. Only after Solomon Snyder and Candace ing drug treatment for schizophrenia until the 1990s. Pert confirmed the presence of receptors could The following two cases illustrate both (1) the use researchers make the conceptual leap linking the of neuroleptics to treat disorders in the spectrum of effects of chlorpromazine/Thorazine to dopamine schizophrenia and (2) the reliance on the dopamine receptors. Snyder, Banerjee, Yamanura, and Green- hypothesis as the cornerstone for treating schizophre- berg (1974) also demonstrated that there were many nia until the early 1990s. This approach met with dopamine receptors, and subsequent research both success and failure, showing that the dopamine showed that antipsychotic drugs had a particular hypothesis was too simplistic. Despite warnings affinity for binding at the dopamine-2 (D2) receptor. from researchers such as Solomon Snyder and Arvid This paved the way for the inordinate focus on Carlsson that the hypothesis was merely a correlation receptors in today’s pharmacologic research. and should not be mistaken for a cause-and-effect Researchers concluded that neuroleptic drugs relationship, by the 1970s the dopamine hypothesis such as chlorpromazine/Thorazine and haloperidol/ of schizophrenia was quite popular. It is still espoused Haldol blocked the D2 receptors, preventing dopa- by some clinicians with great certainty today and that mine from binding at those receptors and exerting an is an error because we also know that agents that effect. Thus, decreasing dopamine activity in this man- block serotonin receptors and glutamate receptors ner lessened symptoms of schizophrenia in many can decrease psychotic symptoms in some but not patients. When researchers assumed that people suffer- all people. The serotonin hypothesis was developed ing from Parkinson’s disease were suffering from by observing that drugs with strong serotonergic decreased dopamine activity, this hypothesis further agonism like lysergic acid diethylamide (LSD) can explained why people taking neuroleptics might suffer cause psychotic-like hallucinations in some but not Parkinsonian side effects. Although the drug they were all users (and these are actually usually visual unlike taking, not Parkinson’s disease, had disrupted their most psychotic hallucinations) and (as noted above) dopamine transmission, the result was the same. newer antipsychotics massively block serotonin and This variation of the dopamine hypothesis was decrease psychotic symptoms in some but not all supported by observations of amphetamine users as people. Finally, the glutamate hypothesis is that well. Researchers had long known that heavy excessive release of excitatory neurotransmitters like amphetamine users could develop symptoms similar glutamate and acetylcholine causes deterioration in to those seen in schizophrenia. Because ampheta- the frontal cortex that causes the symptoms of mines were later shown to increase dopamine in schizophrenia. As Advokat, Comaty, and Julien the synaptic cleft, it made sense that if problems in (2014) conclude “… none of these models dopamine transmission could cause schizophrenia, completely explains nor exactly mimics the pheno- drugs that artificially increased dopamine levels typic presentation of behaviors associated with might cause symptoms similar to those of schizophre- schizophrenia” (p. 340). nia, just as decreased levels of dopamine would cause symptoms similar to those of Parkinson’s disease. To summarize: It is now clear that neuroleptics THE CASE OF COLIN (also called typical antipsychotics) bind to a subfamily of Colin, a 27-year-old father of four, began to notice dopamine receptors called the D2 receptors. Here that he experienced strange thoughts, maybe voices, 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 SEVEN Antipsychotic Medications 155 during his workday. His wife noticed that he was any serious side effects. It is important to note that six more agitated and tense at home, even impatient months after his recovery, Colin found a different with the children. In his work as a media specialist position with more promotion potential and less at a major university, Colin had a range of responsi- stress. As usual though, the medical model perspective bilities linked to a very tight schedule. His schedule provides only part of the story. From the psychologi- had become all but impossible with the layoff of his cal perspective, Colin experienced enormous pressure assistant and he was under the most pressure he had to earn more money for his growing family at the ever been under in his career. His immediate super- same time he learned of his parents’ divorce. He visor noticed his growing disorganization at work also learned there was little promotion potential for and a gradual deterioration of his performance. him at work, and he began to sense a growing stress Colin insisted he was receiving messages that preoc- with his wife. Culturally, Colin, as a second- cupied his mind and distracted him from his daily generation Irishman to the United States, was routine. He became frightened and paranoid, and ashamed of the dramatic nature of his psychological said people were out to destroy him. He stopped disorder and his need to take a psychotropic medica- sleeping and eating, and believed his food was poi- tion. The influence of his family’s rigid interpretation soned. Finally his wife called the emergency room of Catholic dogma made Colin ashamed to share this and was advised to bring Colin in as soon as possible. experience with others. In addition, Colin felt a He resisted her efforts, but finally agreed to go when covert stigmatization at work from his immediate his best friend insisted he should to demonstrate to supervisor, who was Japanese and who failed to the world that he was not insane. grasp the seriousness of Colin’s illness and to be Colin was hospitalized for 18 days and prescribed empathic toward him during his recovery. His super- 24 mg of a typical antipsychotic called thiothixene/ visor also had a work ethic that seemed to view an Navane. Colin also participated in group and art enormous workload as a source of pride rather than therapy during his hospitalization. On release, the burden Colin felt it was. Colin continued the thiothixene/Navane (reduced Therapy was invaluable to Colin as he focused to 12 mg a day) and began individual and couples on some personal issues that bothered him and also therapy at a mental health center. Colin continued worked on many of the difficulties in his marriage. both therapies for several years, stopping the Throughout the therapy, Colin became alert to the thiothixene/Navane after nine months. Ten years signs that indicated that he could become ill again after his hospitalization, Colin remains relatively and, as of this writing, he has had no further serious stable both at work and at home, leading an active problems. and productive life. Colin was never hospitalized again, nor did he decompensate to such a state that he needed to go back on thiothixene/Navane THE CASE OF ETHEL or into the hospital. This episode occurred in the For many years, Ethel suffered from what DSM-IV early 1980s, and the diagnosis at the time was Brief called Undifferentiated Schizophrenia accompanied Reactive Psychosis (what DSM-5 would label Brief with many negative symptoms. Ethel’s psychiatrist Psychotic Disorder). had prescribed 600 mg of chlorpromazine/Thora- Colin’s case also illustrates several of the perspec- zine daily. Because Ethel was single and lived tives we have discussed in this book. He suffered from alone, it was very difficult for her case manager to a brief but serious cognitive impairment that included assess how compliant she was with her medication, hearing voices, losing some contact with reality, and including her benztropine/Cogentin (taken to treat becoming paranoid. From the medical model per- side effects from her chlorpromazine/Thorazine). spective, Colin had psychotic symptoms and was hos- Over a period of two years, Ethel had to be hospi- pitalized for them. The neuroleptic, thiothixene/ talized six times, for periods ranging from eight days Navane, was very helpful, and Colin never developed to four weeks, because she was unable to function 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. 156 PART TWO Introduction or care for herself. Eventually, the pattern became was only partially successful, because many clients clear: Ethel would stop taking her chlorpromazine/ remained resistant to treatment with all neuroleptics Thorazine and gradually retreat into a nonfunction- and/or suffered such serious side effects that neurolep- ing catatonic state. During her last hospitalization, tic treatment became a burden. the treatment team recommended haloperidol/ Haldol by injection on a monthly basis to assist her with compliance. This strategy altered Ethel’s Side Effects of Neuroleptic response to her illness. Although it remained Medication essential for her to take her benztropine/Cogentin Perhaps one of the greatest influences for the devel- orally, getting an injection once a month at the opment of newer antipsychotic medications was the mental health center ended her cycle of hospitali- side effects of the neuroleptic medications. Table 7.1 zations, seemed to ease her negative symptoms, lists the most common neuroleptic drugs still in use and allowed her to participate in group activities today. Note that all these drugs are associated in sponsored by the center. different degrees with the difficult side effects we Neuroleptic therapy by injection was a strategy describe next. implemented for noncompliant patients before the To fully understand the side effects of neurolep- advent of the atypical antipsychotics. This intervention tic antipsychotic medications, we must look at four TABLE 7.1 Examples of Neuroleptic (Typical) Antipsychotics Generic Name Class or Subclass Brand Name Daily Oral Dose Chlorpromazine Phenothiazine (aliphatic) Thorazine 150–1000 mga Promazine Phenothiazine (aliphatic) Sparine 25–1000 mg Triflupromazine Phenothiazine (aliphatic) Vesprin 20–50 mg Fluphenazine Phenothiazine (piperazine) Prolixin 2–20 mg Perphenazine Phenothiazine (piperazine) Trilafon 8–40 mg Trifluoperazine Phenothiazine (piperazine) Stelazine 5–30 mg Mesoridazine Phenothiazine (piperidine) Serentil 75–300 mg Thioridazine Phenothiazine (piperidine) Mellaril 100–800 mg Chlorprothixene Thioxanthene Taractan 30–600 mg Thiothixene Thioxanthene Navane 6–50 mg Haloperidol Butyrophenone Haldol 2–40 mg Molindone Dihydroindolone Moban 20–225 mg © Cengage Learning® Loxapine Dibenzoxazepine Loxitane 30–150 mg Pimozide Diphenylbutylpiperidine Orap 2–12 mg a Schatzberg, Cole, and DeBattista (1997) have summarized research suggesting that little benefit is gained from chlorpromazine by exceeding a dose 400 mg a day. 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 SEVEN Antipsychotic Medications 157 TABLE 7.2 Four Primary Dopamine Pathways in the Brain Name Location Mesolimbic pathway Projects from the ventral tegmental area of the brain to the limbic system. Plays a role in emotional behavior. Mesocortical pathway Projects from the ventral tegmental area of the brain all the way to the cerebral cortex. Plays a role in cognition. Nigrostriatal pathway Projects from the substantia nigra of the brain stem to the basal ganglia and is part of the extrapyramidal nervous system. Tuberoinfundibular pathway Projects from the hypothalamus to the pituitary and governs prolactin release. © Cengage Learning® primary dopamine pathways in the brain that are blunting (sometimes referred to as flat affect) and affected by these medications. Table 7.2 sum- cognitive problems that look like thought disorder. marizes these pathways, and then we discuss each. This has sometimes been called neuroleptic- induced deficit syndrome (Stahl, 2013). The Four Primary Dopamine Neuroleptic-induced deficit syndrome is particu- Pathways in the Brain larly problematic, because it mirrors the negative symptoms of schizophrenia that we discussed at The Mesolimbic Pathway the beginning of this chapter. Part of the ongoing Without dispute, the mesolimbic pathway is most debate is whether neuroleptic medications acting clearly associated with the positive symptoms of on this pathway actually exacerbate the negative schizophrenia. Stahl (2013) has noted that the audi- symptoms of schizophrenia and in turn degrade tory hallucinations, delusions, and even thought the client’s quality of life. Further, if clients have disorder symptoms of schizophrenia have been cor- pronounced negative symptoms before receiving related with this pathway. Stahl has suggested that neuroleptic medication, such medications may perhaps the dopamine hypothesis of schizophrenia make the symptoms worse. should be renamed the “mesolimbic dopamine hypothesis of positive psychotic symptoms” (p. The Nigrostriatal Dopamine Pathway 374), because that more accurately describes the The nigrostriatal dopamine pathway as part of the correlation between neuroleptic medications acting extrapyramidal nervous system governs motor at this brain site and decreased symptoms. Obvi- movements. Any deficiency of dopamine in this ously one problem in medicating clients with pathway causes a movement disorder. Parkinson’s schizophrenia is that the effects of the medications disease is caused by a deficiency of dopamine in (at least to date) cannot be isolated to this one dopa- this pathway, in turn caused by degeneration of mine pathway. dopamine neurons in the pathway. What we describe later as extrapyramidal symptoms are the The Mesocortical Pathway Parkinsonian side effects that result when neu- The mesocortical pathway is related to cognition, roleptic medications block dopamine receptors in but its role (if any) in the symptoms of schizophre- this pathway and cause movement disorders. One nia is undetermined. It does appear that the block- of the more serious disorders is tardive dyskinesia, ade of the dopamine-2 receptors in this pathway or late-appearing abnormal movement. Although by neuroleptic medications causes an emotional the effects of neuroleptics on this pathway 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. 158 PART TWO Introduction thus movement confirmed initial hypotheses about rare side effects. These descriptions should give the role played by dopamine in their mechanism of clinicians a sense of what clients may expect and action, such effects have also confirmed fears that what to listen for as clients describe effects they are for some clients the treatment may be as difficult experiencing. to live with as the symptoms. Allergic Reactions The Tuberoinfundibular or to Neuroleptics Hypothalamic Pathway Allergic reactions to neuroleptics occur in approxi- Ironically, the physically shortest dopamine tract we mately 7% of patients and usually manifest between will discuss has the longest name. The tuberoinfun- two weeks and two months of treatment. The pri- dibular pathway (also called the hypothalamic path- mary symptom is a rash on the face, neck, upper way) is much shorter than the previous three and, as chest, or extremities. The rash (local or general) noted in Table 7.2, controls the prolactin levels that results in red pimples accompanied by a burning normally rise in breast-feeding women. The firing of or stinging sensation. These are usually treated dopamine neurons in this pathway inhibits the release with antihistamines or, in more severe cases, of prolactin, precluding lactation. When a woman is steroids (Malhotra, Litman, & Pickar, 1993). pregnant, part of the hormonal changes she experi- ences include inhibition of these neurons. This inhi- Anticholinergic Effects bition increases prolactin release so the woman can lactate to feed her child after birth. Herein lie more of Neuroleptics problematic side effects from neuroleptic medica- As the name implies, anticholinergic effects of neu- tions. When the medications artificially inhibit the roleptics result from the neuroleptic medication dopamine neurons in this pathway by blocking DA blocking acetylcholine receptors in both the receptors, the result is an unintended increase of pro- peripheral and the central nervous systems. The sec- lactin and symptoms such as galactorrhea (breast ondary results are called autonomic side effects secretion) and amenorrhea (cessation of menses) in because of their impact on the autonomic nervous females as well as development of female secondary system. The primary CNS side effect related to sex characteristics in males. Clients of both genders anticholinergic action is delirium. The peripheral may also experience sexual dysfunction. effects of anticholinergic action are described later. Given this overview of important pathways Note that all these side effects may be exacerbated if affected by neuroleptic medications, you can sur- the client is also taking an anticholinergic agent mise the basic problem. As we noted, the only with the neuroleptic. We explain the rationale for antipsychotic actions from these medications result using these agents later, when we address extrapy- from their blockage of D2 receptors in the meso- ramidal symptoms. limbic pathway. The blocking of D2 receptors in the remaining three pathways result in undesirable Blurred Vision side effects. In addition, neuroleptics are “dirty” The anticholinergic action of neuroleptics can para- drugs, meaning that they not only block dopamine lyze the ciliary muscle in the pupil of the eye, caus- receptors but also may block histamine, acetylcho- ing difficulty in focusing on objects within a close line, and adrenergic receptors. These properties field of vision. Sometimes prescribers lower the dos- also result in undesirable side effects. Having intro- age temporarily or recommend reading glasses to duced the different ways in which side effects can provide relief (Perry, Alexander, & Liskow, 2006). occur from neuroleptic medication, let’s now look We have found that although not all clients experi- more closely at the primary side effects of these ence this (or any other side effect), those who do medications. Please note that this discussion of often prefer to have the doctor change their medica- the topic is not exhaustive and does not include tion (and honestly who can blame them?). 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 SEVEN Antipsychotic Medications 159 Dry Mouth tapered off if it is to be discontinued. Perry et al. Dry mouth can be particularly bothersome for cli- (2006) recommend at least a one-week period (inpa- ents, depending on the strength of the effect. Both tient) or a two-week period (outpatient) where the the antihistaminic and anticholinergic effects of dosage is titrated down before the drug is discontin- neuroleptics cause dry mouth. Many clients can ued. Although it is more associated with the atypical obtain relief with sugarless gum or candy, but antipsychotics, hypersalivation can also occur in peo- many clients find it necessary to carry a drinking ple taking neuroleptics. Essali and colleagues (2013) bottle with them at all times. Our clients often pre- have noted that this is an understudied phenomenon ferred sweetened, caffeinated soft drinks, which, and although they believe anticholinergic drugs may combined with other poor dietary habits, exacer- be helpful, more research is necessary. bated the weight gain associated with the antihista- minic effects of neuroleptics. Cardiovascular Side Effects from Neuroleptics Constipation Constipation can be seriously aggravated by neuro- As with some of the antidepressants we discussed in leptic medication, although it may resolve as the Chapter Five, neuroleptics can cause orthostatic client adjusts to the medication. Routine use of hypotension, which is due to the antiadrenergic laxatives is to be discouraged (Perry et al., 2006). effects of these drugs. This effect inhibits the normal Malhotra and colleagues (1993) noted that in severe constriction of blood vessels associated with postural cases, constipation can progress into fatal intestinal change, resulting in the lightheadedness and dizzi- dilation or paralytic ileus. Paralytic ileus can result ness characteristic of orthostatic hypotension (Mal- in death through intestinal obstruction. Although hotra et al., 1993). This side effect usually begins this is rare, clients need regular checkups with within the first few hours or days of treatment regard to intestinal functioning. and is more pronounced when the neuroleptic has been administered parenterally (by injection). In Urinary Retention most cases, clients can easily manage this by stand- Urinary retention may be noticed two to four ing up slowly and by elevating their feet when lying weeks from beginning the neuroleptic regimen. down. In cases where clients have complained According to Perry and colleagues (2006), block- about this effect, lowering the medication dose ing the acetylcholine neurons affects the detru- has also been effective as long as the therapeutic sor muscle that governs the flow of urine. effects are not diminished to the point that symp- Although the effect is dose related, acute urinary toms begin to interfere with the client’s life again. retention is a sign for the prescribing profes- Clients on neuroleptics may also experience elec- sional to consider another medication as it can trocardiogram changes, which are of debatable clin- lead to kidney problems and bladder or urinary ical significance. Although case reports exist of tract infections. lethal cardiovascular events in people taking neuro- leptics, they have not been linked to the neurolep- Withdrawal Reactions tic medication per se. Although neuroleptic medications are not drugs of abuse per se, regular and long-term use can induce Dermatological Side Effects tolerance, which can lead to withdrawal reactions if from Neuroleptics medications are discontinued abruptly. The symptoms Perhaps the most common dermatologic side effect is usually begin two or three days after discontinuation photosensitivity. This sensitivity to sunlight occurs in and include headache, nausea, vomiting, diarrhea, and approximately 3% of clients taking neuroleptic med- insomnia. Any client who has taken a neuroleptic for ications. Most cases are related to chlorpromazine/ at least one month should have the medication Thorazine, but all clients on neuroleptics should 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. 160 PART TWO Introduction limit their exposure to the sun and should use sun- Extrapyramidal Symptoms Caused by screen and protective clothing. Approximately 1% of Neuroleptic Medication clients on neuroleptics develop a bluish pigmentation As you may recall from our discussion of the nigros- in their skin. This rare effect depends on the neuro- triatal dopamine pathway in the brain, neuroleptic leptic used, dosage, and extent of exposure to sun- medications block the dopamine-2 receptors in this light. These disorders are thought to be much less pathway and cause movement disorders. These frequent today because use of neuroleptics has EPSs, can range from mild to severe, and may decreased and lower doses are used (Perry et al., have early or late onset. For most clients, these 2006). symptoms are problematic and are one reason that many psychiatrists believe newer, atypical antipsy- Endocrinological Side Effects chotics should be the first line of treatment. of Neuroleptic Medications Neuroleptics can cause hormonal side effects partly Early-Onset Extrapyramidal Symptoms because of their impact on dopamine transmission Estimates of early-onset EPSs fluctuate wildly, in the tuberoinfundibular pathway, described ear- ranging between 2 and 95% of clients taking neu- lier. As mentioned, galactorrhea and amenorrhea roleptics (Lavin & Rifkin, 1992). Dystonias or can occur in females. It is important to note that dystonic reactions occur in 2 to 10% of clients breast enlargement and engorgement can occur in on neuroleptic medications. The onset is sudden both males and females (Sullivan & Lukoff, 1990). (1 to 3 days after neuroleptic medication is taken) Elevated prolactin levels may subside within two to and consists of involuntary contractions of possi- three days of discontinuing treatment of oral anti- bly any striated muscle group. The most common psychotics, but in some cases this may take weeks or dystonic reactions are in the muscles of the head months (Perry et al., 2006). In addition, clients may and face, producing tics, facial grimacing, or experience polydipsia (excessive thirst and water spasms. The reactions are possible with all neuro- drinking) or a deficiency of sodium in the blood leptics but are less likely with the piperazine phe- (hyponatremia). nothiazines (e.g., fluphenazine/Prolixin) (see Table 7.1). Although these side effects often Weight Gain cease without treatment, they can be easily treated Studies done in the 1970s correlated weight gain with Benadryl or benztropine/Cogentin, an anti- with neuroleptic medications. The average gain cholinergic agent. The etiology of dystonic reac- was approximately 13 pounds. Weight gain is tied tions is not known. to the antihistaminic properties of the neuroleptics, The term akathisia refers to a subjective experi- as is drowsiness and sedation (Advokat et al., 2014), ence of motor restlessness, a condition that is much but it can be exacerbated by poor choices like sug- more difficult to treat than dystonic reactions. In our ary drinks to ease side effects like dry mouth. Perry clinical work with clients, the psychological experi- et al. (2006) caution that although weight gain may ence of this particular side effect can be profound. be a property of neuroleptic medications, it may Clients report feeling that they cannot sit still, and also be due to a combination of factors such as they tap their foot/feet, pace back and forth, shake the medication, a sedentary lifestyle, and poor diet their hands, or rock back and forth when standing. habits. Although these authors encourage clinicians Observed behaviorally, they are always in constant to monitor patients’ weight, they remind us that motion. The incidence of akathisia in studies ranges under no circumstances should clients use from 21 to 75% (Perry et al., 2006). The majority of amphetamine-based appetite suppressants, because clients who develop akathisia experience symptoms of the connection between dopamine stimulation within about two months. Schatzberg et al. (1997) and exacerbated symptoms. note that sometimes akathisia has been misdiagnosed 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 SEVEN Antipsychotic Medications 161 as psychotic agitation. Obviously, this misdiagnosis Late-Onset Extrapyramidal Symptoms may lead doctors to increase the dosage of the very Two identified late-onset EPSs are similar to the compound causing the problem. early-onset symptoms and differ only in the time it One sign from which to discern the difference takes them to manifest. Frequently these are between psychotic agitation and akathisia is the called tardive syndromes, meaning delayed-onset, degree of psychological contact the client can make. abnormal, and involuntary movement disorders It is important that someone who has a therapeutic (Fernandez & Friedman, 2003). Bear in mind that alliance with the client talk to him or her about the the word tardive means “late appearing”; thus, tardive symptoms. Most clients suffering from akathisia can, dystonia and tardive akathisia are the same as dystonic to some extent, describe the symptoms and differen- reactions and akathisia as described earlier, but with a tiate them from psychotic symptoms they have expe- much later onset (sometimes after a patient has taken rienced in the past. Schatzberg and colleagues note the neuroleptic for years). Although there is no that asking the client whether the restlessness is “a developed literature regarding these two late-onset muscle feeling or a head feeling” (p. 145) often EPSs, there is a great deal of literature on tardive helps differentiate akathisia (the muscle feeling) from dyskinesia. anxiety that may accompany agitation (the head feel- Tardive dyskinesia is a late-appearing abnormal ing). These authors consider that to assume akathisia movement of the mouth, lips, and tongue that may over agitation is to err on the side of caution. Doctors be accompanied by involuntary twitching and jerking may treat akathisia with a benzodiazepine, an anti- of muscles (choreic movement). The primary differ- Parkinsonian agent such as benztropine/Cogentin, ential diagnoses include Huntington’s chorea and or even a beta-blocker such as propranolol/Inderal. other disorders that affect the basal ganglia (Casey, Although some clients may not even be aware of 1993). The most common symptoms are sucking their akathisia, the symptoms greatly distress others. and smacking lip movements, lateral movements of Furthermore, sometimes agents used to treat akathisia the jaw, and puffing of cheeks with tongue-thrusting exacerbate the sedation the client experiences, mak- motions (Perry et al., 2006). Tardive dyskinesia ing such treatment problematic. affects on average 15 to 20% of clients on neurolep- Parkinsonism is a set of side effects that manifest tics, although gender (7:1 male-to-female ratio), age, as muscular rigidity, slowed movement, tremors diagnosis, dosage, and duration of neuroleptic regi- (usually in the hands), or bradykinesia (fatigue men all seem to play a role. Perry and colleagues when performing repetitive motion). The tremors (2006) noted, tardive dyskinesia is seen in approxi- may occur at rest or while in motion and may mately 5–10% of patients being treated with neuro- include the mouth, chin, and lips. Clients with Par- leptics who are over 40 years of age but can also kinsonism appear depressed, but it is important to occur in up to 80% of elderly patients. In general, differentiate this from actual depression. The inci- people with schizophrenia (likely due to the drugs dence ranges in studies from 2 to 56% of clients they are taking) have a 31 times higher chance of taking neuroleptics. Again it depends on the neu- developing tardive dyskinesia than those in the gen- roleptic used, the dosage, and the individual’s eral population (Merrill, Lyon, & Matiaco, 2013). response to it. Parkinsonism is typically treated There are several theories of etiology for tardive with anticholinergic agents (such as benztropine/ dyskinesia, including hypersensitivity to dopamine, Cogentin). There is debate as to whether or not imbalances between the dopamine and acetylcho- all neuroleptics should be given with an anti- line systems, GABA dysfunction, and excitotoxi- Parkinsonian agent (Stanilla & Simpson, 1995). city. Most recently, a theory has been proposed Advocates claim that doing so precludes the appear- that oxidative stress and resulting structural abnor- ance of many extrapyramidal symptoms, and oppo- malities are the key factors in people who develop nents claim the neuroleptics are toxic enough tardive dyskinesia (Kulkarni & Naidu, 2003). At without adding a second agent if not needed. present, there is no one accepted theory. 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. 162 PART TWO Introduction Tardive dyskinesia is unpredictable. Although a and autonomic disturbances characterize NMS. six-month regimen of neuroleptics is generally con- Caroff and Mann (1993) have noted that the sidered safe, some patients develop tardive dyskine- onset may occur within an hour to two months sia after only a few weeks of taking neuroleptics. after the first dose of the neuroleptic. In most When clients show signs of tardive dyskinesia and cases, the clients show signs within a week. Once the neuroleptic is discontinued, often the symptoms NMS begins, it progresses rapidly over a one- to vanish within weeks to months. Tardive dyskinesia three-day period. If the medication is discontinued appears irreversible in some cases, whereas in others in time, most cases resolve within a month. Fatali- it may only remit years after the neuroleptic is dis- ties from NMS are rare, because use of neuroleptics continued. Schatzberg et al. (1997) noted that has decreased and the syndrome is detected early. about 25% of their clients developed dyskinesia when the neuroleptic was tapered off or stopped. Agents to Treat Extrapyramidal Side Effects Dyskinesia develops in some individuals who have Anti-Parkinsonian agents are used for treating never been exposed to neuroleptics (Merril et al., early-onset extrapyramidal symptoms. Recall that 2013). Schatzberg and colleagues (1997) state there these side effects result from neuroleptic-induced is no single effective or standard treatment for tard- blockade of dopamine receptors in the nigrostriatal ive dyskinesia and clinicians should consider the pathway that cause decreased dopamine transmis- risks and benefits of extended treatment with neu- sion. Table 7.3 lists drugs commonly used to treat roleptics in patients likely to be kept on the medi- EPSs. More recently, experimental studies have cation more than a few months. been conducted to examine calcium channel block- Schatzberg