New Developments in Antipsychotic Therapy

CME

ACADEMIC HIGHLIGHTS New Developments in Antipsychotic Therapy

Evolution of Antipsychotic Therapy: A Mechanism-Based Evaluation his ACADEMIC HIGHLIGHTS section of The Journal of Clinical T Psychiatry presents the W. Wolfgang Fleischhacker, M.D., the development of aripiprazole, a par- highlights of the teleconference “New began the meeting by reviewing the tial D2 agonist, which has been shown history of the mechanism-based de- to be an effective treatment in schizo- Developments in Antipsychotic Therapy,” velopment of antipsychotic drugs. phrenia patients.2,3 held September 25, 2003. Mechanism-based studies commenced Other research, Dr. Fleischhacker The teleconference was chaired by with Paul Janssen’s clinical observa- pointed out, has examined agents that Peter J. Weiden, M.D., Department of tion in Belgian cyclists that the dopa- have no direct effect on the dopamine Psychiatry, State University of New York mine agonist amphetamine led to psy- system, although most of them have Downstate, Brooklyn, N.Y. The faculty chosis and abnormal movements indirect effects on dopaminergic path- were W. Wolfgang Fleischhacker, M.D., similar to those seen in schizophrenia ways. The putative antipsychotic ac- Department of Psychiatry, Innsbruck patients. Expanded knowledge about tion of these drugs has been studied as University Clinics, Austria; John M. the pathophysiology of schizophrenia, both monotherapy and add-on treat- Kane, M.D., Department of Psychiatry, especially the development and accep- ment. Dr. Fleischhacker presented a The Zucker Hillside Hospital, Glen Oaks, tance of the dopamine hypothesis, has list of these agents categorized by N.Y.; Stephen R. Marder, M.D., also motivated more mechanism-based mechanism of action (Table 2), and Department of Psychiatry, West Los research. After the success of cloza- discussed some of the more promising Angeles Veterans Affairs Medical Center, pine, which has a number of pharma- agents—serotonin antagonists, N- Calif.; J. Michael Ryan, M.D., Monroe cologic actions beyond blocking dopa- methyl-D-aspartate (NMDA) glutamate Community Hospital, Rochester, N.Y.; mine receptors, the focus shifted to receptor agonists, omega-3 fatty acids, and Stephen M. Strakowski, M.D., other transmitter systems. According and hormones—in more detail. Department of Psychiatry, University to Dr. Fleischhacker, all of this re- of Cincinnati, Ohio. search, along with advances in psycho- Serotonin Antagonists This ACADEMIC HIGHLIGHTS was social therapies, has led to several new Dr. Fleischhacker noted that a num- independently developed by the treatment approaches to schizophrenia ber of serotonin (5-HT) antagonists Physicians Postgraduate Press, Inc. (Table 1). have been tried as add-on therapy in Office of Continuing Medical Education More recent research in schizophre- patients suffering from schizophrenia, nia has focused on the various sub- although largely without success pursuant to an unrestricted educational systems of dopamine neurotransmis- against the full spectrum of symptoms. grant from Bristol-Myers Squibb. sion,1 reported Dr. Fleischhacker. Whereas some results show that these Financial disclosure appears at the However, except for the successful 5-HT antagonists, especially 5-HT an- end of this article. 2 development of specific dopamine D2 tagonists, were effective treatments for The opinions expressed herein are antagonists such as the benzamide negative symptoms,4 other studies those of the authors and do not amisulpride, research into other spe- show the opposite.5 necessarily reflect the views of the CME cific dopamine receptor subsystems provider and publisher or the commercial has been largely unsuccessful. Specific Glutamate Receptor Agonists supporter. D4 or D1 antagonists, for example, have Another system that has been not been clinically effective. The most explored in schizophrenia, Dr. recent addition to the attempts to Fleischhacker explained, is the gluta- modulate dopaminergic transmission is mate neurotransmitter system. Since

J© Clin COPYRIGHT Psychiatry 2003 64:11, PHYSICIANS November P OSTGRADUATE2003 PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. 1379 ACADEMIC HIGHLIGHTS

Table 1. New Treatment Approaches in Table 2. Putative Antipsychotics schizophrenia pharmacotherapy is still Schizophrenia With No Direct Effect on Dopamine blockade of D2 receptors. However, Antipsychotics that are chemically Receptors the advent of partial agonists at the similar to existing treatments Serotonin antagonists dopamine D2 receptor have greatly New administration routes for Ritanserin enhanced the possibility of treating second-generation antipsychotics MDL 100,907 psychosis. In addition, agents with Newly discovered pharmacologic N-methyl-D-aspartate (NMDA) agonists mechanisms Glycine other mechanisms of action that have Pharmacologic add-on strategies D-Serine been mainly tried as add-on therapies New psychosocial interventions D-Cycloserine thus far seem to be effective against Combination of pharmacologic and Omega-3 fatty acids some of the specific subsyndromes of psychosocial interventions DHA (docosahexaenoic acid) Availability of all of the above EPA (eicosapentaenoic acid) schizophrenia such as negative and to all patients Hormones affective symptoms as well as cogni- Estrogen tive impairment. Neuropeptide agonists γ-Endorphin postmortem glutamate levels are low γ-Aminobutyric acid (GABA) agonists REFERENCES in patients who had schizophrenia and Diazepam Bretazenil 1. Fleischhacker WW. New developments since receptor antagonists of NMDA in the pharmacotherapy of schizophrenia. Norepinephrine antagonists (a subtype of the glutamate receptor) J Neural Transm Suppl 2003;64:105Ð117 Idazoxan 2. Kane JM, Carson WH, Saha AR, et al. induce schizophrenia-like symptoms, σ Receptor Antagonists Efficacy and safety of aripiprazole and it is thought that glutamate dysfunc- Rimcazole haloperidol versus placebo in patients with tion is part of the pathophysiology of Panamesine schizophrenia and schizoaffective disor- 6 der. J Clin Psychiatry 2002;63:763Ð771 schizophrenia. In fact, the addition 3. Potkin SG, Saha AR, Kujawa MJ, et al. 7 8 of agents such as glycine, D-serine, Aripiprazole, an antipsychotic with a 9 and D-cycloserine to ongoing anti- reached menopause. In addition, novel mechanism of action, and risperi- done vs placebo in patients with schizo- psychotic treatment has been shown women have a lower risk of relapse phrenia or schizoaffective disorder. Arch to decrease the severity of negative during pregnancy.14,15 The epidemiol- Gen Psychiatry 2003;60:681Ð690 symptoms and possibly cognitive ogy and course of schizophrenia in 4. Duinkerke SJ, Botter PA, Jansen AA, et al. Ritanserin, a selective 5-HT2/1C impairment. women, then, would imply that estro- antagonist, and negative symptoms in gen has an effect on the illness. Pilot schizophrenia: a placebo-controlled Omega-3 Fatty Acids studies of estrogen as a treatment for double-blind trial. Br J Psychiatry 1993;163:451Ð455 Dr. Fleischhacker explained that schizophrenia have produced inconsis- 5. Den Boer JA, Vahlne JO, Post P, et al. phospholipids are vital compounds of tent yet encouraging results.16Ð18 Ritanserin as add-on medication to neuro- leptic therapy for patients with chronic or cell membranes. These phospholipids subchronic schizophrenia. Hum can break down due to oxidative stress, Dopamine-2 Partial Agonists Psychopharmacol 2000;15:179Ð189 resulting in cell membrane damage, According to Dr. Fleischhacker, the 6. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology which in neurons can lead to impaired only new mechanism-based agent that and treatment of schizophrenia. neuronal function. Neuronal damage has been proven clinically efficacious Am J Psychiatry 2001;158:1367Ð1377 may in turn explain the psychosis of is one developed as a partial agonist of 7. Heresco-Levy U, Javitt DC, Ermilow M, et al. Efficacy of high-dose glycine in the schizophrenia. A diet low in calories the dopamine D2 receptor, the new treatment of enduring negative symptoms and supplemented by antioxidants and atypical antipsychotic aripiprazole. of schizophrenia. Arch Gen Psychiatry unsaturated fatty acids may correct Aripiprazole is a high-affinity partial 1999;56:29Ð36 8. Coyle JT, Tsai G, Goff DC. Ionotropic phospholipid damage; this correction agonist at D2 receptors. Under condi- glutamate receptors as therapeutic targets in patients with schizophrenia should tions of dopamine hyperactivity, it in schizophrenia. Curr Drug Target CNS theoretically improve illness out- functions as a dopamine antagonist, Neurol Disord 2002;2:183Ð189 10 9. Evins AE, Amico E, Posever TA, et al. comes. However, according to Dr. and under conditions of dopamine D-Cycloserine added to risperidone in pa- Fleischhacker, large clinical trials with hypoactivity, it functions as a dopa- tients with primary negative symptoms of the omega-3 fatty acids docosahexa- mine agonist.19 This antipsychotic has schizophrenia. Schizophr Res 2002;56: 11 19Ð23 enoic acid (DHA) and eicosapen- demonstrated efficacy and safety in 10. Mahadik SP, Evans D, Lal H. Oxidative taenoic acid (EPA)11Ð13 have provided treating both the positive and negative stress and role of antioxidant and omega-3 essential fatty acid supplementation in inconsistent results. symptoms of schizophrenia when com- schizophrenia. Prog Neuropsycho- pared with placebo, haloperidol, and pharmacol Biol Psychiatry 2001;25: Hormones risperidone.2,3 463Ð493 11. Peet M, Brind J, Ramchand CN, et al. Dr. Fleischhacker noted that women Two double-blind placebo-controlled pilot with schizophrenia are older than men Conclusion studies of eicosapentaenoic acid in the at onset of the illness, and symptoms A number of mechanisms of action treatment of schizophrenia. Schizophr Res 2001;49:243Ð251 seem to be tied to the menstrual cycle have been explored during the past 30 12. Fenton WS, Dickerson F, Boronow J, among women who have not yet years. The most successful target in et al. A placebo-controlled trial of omega-

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3 fatty acid (ethyl eicosapentaenoic acid) 16. Kulkarni J, de Castella A, Smith D, et al. initial dose escalation of olanzapine supplementation for residual symptoms and A clinical trial of the effects of estrogen in cognitive impairment in schizophrenia. Am acutely psychotic women. Schizophr Res (up to 40 mg/day on days 1 and 2, up J Psychiatry 2001;158:2071Ð2074 1996;20:247Ð252 to 30 mg/day on days 3 and 4, and up 13. Emsley R, Myburgh C, Oosthuizen P, et al. 17. Kulkarni J, Riedel A, de Castella AR, et al. to 20 mg/day thereafter) or usual clini- Randomized, placebo-controlled study of A clinical trial of adjunctive oestrogen ethyl-eicosapentaenoic acid as supplemen- treatment in women with schizophrenia. cal practice. Agitation in both groups tal treatment in schizophrenia. Am J Arch Women Ment Health 2002;5:99Ð104 of patients had decreased significantly Psychiatry 2002;159:1596Ð1598 18. Lindamer LA, Buse DC, Lohr JB, et al. after 24 hours, but patients on the rapid 14. Hafner H, Maurer K, Loffler W, et al. Hormone replacement therapy in postmen- The epidemiology of early schizophrenia: opausal women with schizophrenia: posi- dose escalation treatment saw a greater influence of age and gender on onset and tive effect on negative symptoms? Biol benefit than did those on treatment as early course. Br J Psychiatry 1994;164 Psychiatry 2001;49:47Ð51 usual. (suppl 23):29Ð38 19. Burris KD, Molski TF, Xu C, et al. Ari- 15. Riecher-Rössler A. Oestrogen effects in piprazole, a novel antipsychotic, is a high- Dr. Weiden pointed out that adding schizophrenia and their potential therapeu- affinity partial agonist at human dopamine a different type of medication to anti- tic implications: review. Arch Women D2 receptors. J Pharmacol Exp Ther psychotic treatment may be another Ment Health 2002;5:111Ð118 2002;302:381Ð389 way to boost response. A combination study3 showed that adding divalproex to acute treatment with either risperi- done or olanzapine led to more rapid Acute Treatment of Schizophrenia acute psychotic symptom resolution than either antipsychotic alone. Sev- Peter J. Weiden, M.D., discussed treated group had lower rates of extra- eral strategies, then, are available that new developments in the treatment of pyramidal symptoms (EPS); fewer can hasten response and bring about acute psychosis. Treatment of this movement disorders and lower rates of earlier reduction of symptoms than we phase includes controlling agitation use of anticholinergic medications see in usual clinical practice. and psychosis immediately, ensuring were noted in the ziprasidone-treated rapid and sustained response to treat- group. Although moderate QTc in- Broad-Spectrum Efficacy ment, and treating all types of symp- creases have been reported with zi- of Atypical Antipsychotics toms. prasidone treatment, this study of the Dr. Weiden then discussed the One area of interest in acute treat- i.m. formulation found similarly low newest antipsychotic, aripiprazole, ment is the examination of why some increases in QTc in both ziprasidone- which has been shown to be as effec- physicians rely on conventional anti- and haloperidol-treated patients. tive as the older comparator haloperi- psychotics early in treatment and Dr. Weiden noted that short-acting dol.4 A recent study5 also found that whether short-acting intramuscular i.m. formulations of other atypical anti- aripiprazole, 20 or 30 mg/day, was as (i.m.) formulations of atypical antipsy- psychotics are currently being studied. efficacious as 6 mg/day of risperidone. chotics will meet those needs. Another For example, i.m. olanzapine is in the Patients treated with either agent ex- area of research in acute treatment of final stage of development and study perienced a significant decrease in schizophrenia is the possibility of rapid of i.m. aripiprazole has started. He ar- Positive and Negative Syndrome Scale response, by either rapid dose escala- gued that with the better EPS profile (PANSS) total scores, positive scores, tion or concomitant treatment with a of the atypicals compared with con- and negative scores compared with different type of agent. An effective ventional drugs as well as the new placebo. In the aripiprazole groups, treatment should not only address black box warning on the older agent the separation from placebo in PANSS acute psychosis and agitation, but it droperidol, i.m. formulations of atypi- negative subscale scores occurred at should also alleviate negative and cal antipsychotics may be the new week 1; in the risperidone-treated mood symptoms. Lastly, atypical anti- standard of care when treating acute group, this separation occurred at psychotic doses should be optimized psychosis. week 2 (Figure 1). In addition, pa- to ensure the best possible response. tients treated with aripiprazole ex- Rapid Response perienced few EPS and little-to-no Short-Acting Intramuscular Another area of interest, according weight gain or serum prolactin level Formulations of Atypical to Dr. Weiden, is the attempt for a increases. Antipsychotics more rapid response to oral atypical Dr. Weiden argued that these effi- Dr. Weiden noted that the first antipsychotic treatment in the first cacy results support the notion that short-acting i.m. atypical antipsychotic week or so of treatment. For many results from short-term, atypical anti- available in the United States is zipra- agents, the rapidity of response may be psychotic trials look more similar than sidone. In one study,1 symptom reduc- related to a rapid titration schedule. For different in the acute phase of the ill- tion was significantly greater in the example, a recent study2 examined ness. Although the atypicals have group treated with ziprasidone i.m. olanzapine as an acute treatment for more broad-spectrum efficacy, they do than in the group treated with haloperi- agitated patients with psychosis or not match clozapine for efficacy dol i.m. In addition, the ziprasidone- mania. Patients received either rapid against the most severe persistent posi-

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Neuropsychopharmacology 2003;28: Figure 1. Mean Change in PANSS Negative Scores From Baseline During 4 Weeks 182Ð192 of Treatment with Aripiprazole, Risperidone, or Placeboa 4. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and 0 haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. –1 J Clin Psychiatry 2002;63:763Ð771

ANSS † 5. Potkin SG, Saha AR, Kujawa MJ, et al. –2 * Aripiprazole, an antipsychotic with a novel ‡ † † † † mechanism of action, and risperidone vs –3 † † ‡ † placebo in patients with schizophrenia or schizoaffective disorder. Arch Gen –4 Placebo Psychiatry 2003;60:681Ð690 Aripiprazole 20 mg –5 Aripiprazole 30 mg 6. Kane J, Honigfeld G, Singer J, et al. Mean Change in P in Change Mean Risperidone 6 mg Clozapine for the treatment-resistant

Negative Score From Baseline From Score Negative –6 schizophrenic: a double-blind comparison 01234 with chlorpromazine. Arch Gen Psychiatry 1988;45:789Ð796 Week 7. Small JG, Hirsch SR, Arvanitis LA, et al, aReprinted with permission from Potkin et al.5 for the Seroquel Study Group. Quetiapine *p < .05 vs. placebo. †p < .01 vs. placebo. ‡p < .001 vs. placebo. in patients with schizophrenia: a high- and Abbreviation: PANSS = Positive and Negative Syndrome Scale. low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997;54:549Ð557 8. Goff DC, Posever T, Herz L, et al. An exploratory haloperidol-controlled dose- tive symptoms. For example, Kane and Conclusion finding study of ziprasidone in hospitalized coworkers6 found that clozapine was The study of schizophrenia and the patients with schizophrenia or schizoaffec- tive disorder. J Clin Psychopharmacol significantly more effective in treating measurement of its symptoms have not 1998;18:296Ð304 positive and negative symptoms of changed at the same pace, Dr. Weiden 9. Keck P Jr, Beffenstein A, Ferguson J, et al. schizophrenia than the conventional stated. Although clinicians and re- Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and agent chlorpromazine. Although many searchers are more and more concerned schizoaffective disorder: a 4-week placebo- studies of atypical agents have used with finding ways to treat the negative controlled trial. Psychopharmacology that basic design—comparing the symptoms, mood symptoms, and cog- (Berl) 1998;140:173Ð184 10. Lieberman J, Carson WH, Saha AR, atypical to the conventional after a pro- nitive dysfunction associated with et al. Meta-analysis of the efficacy spective lead-in with another antipsy- schizophrenia, the standard outcome of aripiprazole in schizophrenia. Int J chotic to establish nonresponse—they scales have not changed. In addition, Neuropsychopharmacol 2002;5(suppl 1): S186 have not shown the kind of effects that clinicians and researchers are more were shown with clozapine. Dr. aware of side effects and their effects Weiden offered that psychiatry is still on a patient’s health and quality of looking for another clozapine without life. While more research is clearly Diagnostic Boundaries its dangerous side effects, and that the needed in antipsychotic medications, newer medicines available now have cognitive-behavioral therapies may be Between Bipolar Disorder not achieved that goal. able to improve symptoms over and and Schizophrenia above what medication can do alone. Optimal Dosing When moving beyond the acute phase, Stephen M. Strakowski, M.D., ad- Dr. Weiden said that the under- then, promising approaches exist that dressed the challenges of distinguish- standing of how to best dose these combine medicines with certain kinds ing between bipolar disorder and newer medications—in particular, que- of psychosocial treatments, and it may schizophrenia. The conditions share tiapine, ziprasidone, and aripipra- be that the best outcomes will be the many symptoms, which makes diag- zole—continues to evolve. Quetiapine7 result of these combinations. nosis difficult, especially in patients and ziprasidone8,9 seem to have a lin- experiencing their first episode of psy- ear dose response curve within the REFERENCES chosis. Fortunately, second-generation therapeutic range, such that higher antipsychotics appear to be effective 1. Brook S, Lucey JV, Gunn KP, for the Zi- doses will move a patient toward prasidone I.M. Study Group. Intramuscular for both disorders, although Dr. higher levels of response. In contrast, a ziprasidone compared with intramuscular Strakowski emphasized that effective meta-analysis of aripiprazole10 shows haloperidol in the treatment of acute psy- treatments are not a replacement for chosis. J Clin Psychiatry 2000;61:933Ð941 that equivalent efficacy occurs across 2. Baker RW, Kinon BJ, Maguire GA, et al. accurate diagnosis. the therapeutic range, from 15 to 30 Effectiveness of rapid initial dose escala- tion of up to forty milligrams per day of A Historical Perspective mg/day. These controlled trials are oral olanzapine in acute agitation. J Clin helpful to establish reasonable dosing Psychopharmacol 2003;23:342Ð348 Dr. Strakowski began by pointing parameters. The antipsychotic treat- 3. Casey DE, Daniel DG, Wassef AA, et al. out that almost a hundred years ago, Effect of divalproex combined with olanza- 1 ment should then be adjusted to opti- pine or risperidone in patients with an Emil Kraepelin attempted to distin- mize individual patient response. acute exacerbation of schizophrenia. guish between bipolar disorder and

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schizophrenia when he differentiated Table 3. Bipolar Disorder and new-onset psychotic illness is difficult manic-depressive insanity from what he Schizophrenia: Common Symptoms because there is no prior psychiatric called dementia praecox, which has Psychotic history, so no course of illness data more or less evolved into the current Depressive exist. Another complicating factor in diagnosis of schizophrenia. Kraepelin Manica first-episode psychosis is that patients primarily based this distinction on the Neurovegetative and their families are confused: the Cognitive differences in the course of illness that Negativeb patient does not understand what is the conditions exhibited; that is, pa- aManic syndrome is relatively specific for bipolar happening and the family has never tients with manic-depressive insanity disorder. seen this behavior in the patient. bNegative syndrome is relatively specific for showed a recovery between acute ex- schizophrenia. Therefore, the psychiatrist has little acerbations, whereas patients with de- information with which to make a mentia praecox showed a more deterio- diagnosis, so preliminary diagnoses rating, chronic course. Depressive symptoms are also com- are often assigned on the ability to Although Kraepelin’s distinction mon to both disorders. Almost all pa- identify the relative prominence of was an advance in psychiatry, practi- tients with schizophrenia will develop manic or depressive symptoms, which cally and clinically it was not particu- depressive episodes at some point in often are upstaged in acute psychosis larly helpful. Clinicians could not wait their course of illness. Mania, one of by the more dramatic psychotic symp- the many years necessary to determine the most specific syndromes in psychi- toms. Occasionally, family history in- a course of illness before diagnosing, atry and a relatively good predictor of formation is helpful, but unfortunately treating, and prognosticating the illness. a bipolar course, may unfortunately many patients with bipolar disorder Therefore, throughout much of the rest resemble an acute agitated psychotic often have schizophrenia in their fam- of the century, a significant effort was exacerbation of schizophrenia. Both ily and vice versa. made to identify ways to separate what conditions share neurovegetative In light of the difficulties associ- are now known as bipolar disorder and symptoms and signs as well as cogni- ated with differentiating between bi- schizophrenia from each other through tive disabilities. Finally, schizophrenia polar disorder and schizophrenia, cli- different symptoms and symptom con- has a relatively specific negative syn- nicians must try to make the best structs, which evolved into the Interna- drome, but in clinical practice, this diagnosis possible and then identify tional Classification of Disease and negative syndrome can be difficult to the most useful treatment, recognizing Diagnostic and Statistical Manual of distinguish from bipolar depression. that approximately 15% of patients Mental Disorders criteria. With so many shared symptoms, the who are diagnosed with either affec- For most of the 20th century, re- course of illness really is the determin- tive psychosis or schizophrenia will be ported Dr. Strakowski, distinguishing ing factor differentiating these condi- assigned another diagnostic category between bipolar disorder and schizo- tions, but clinicians cannot wait to see within 1 to 2 years.2 Further, patients phrenia was an academic exercise be- what the course is going to be before with schizophreniform disorder, a cause the treatments for the disorders deciding upon treatment. Complicat- diagnosis frequently given to patients were not particularly different. It was ing diagnosing bipolar disorder and with first-episode psychosis and often not until the development of lithium as schizophrenia is that a large number of thought of as a category for people a treatment that making the distinction patients do not fit neatly in either who will develop schizophrenia, go on became important; people with bipolar group, and those patients, who bridge to develop conditions other than disorder responded quite well to lith- the 2 groups, are therefore diagnosed schizophrenia, primarily affective psy- ium, whereas those with schizophrenia as schizoaffective disorder patients. chosis, at a rate of about 40%.3 did not. Recently, an alternate approach has suggested that affective illness is a con- Treating Patients With Shared Symptoms of Bipolar tinuum with schizophrenia at the se- New-Onset Psychosis Disorder and Schizophrenia vere end and unipolar depression at the Dr. Strakowski reminded clinicians Dr. Strakowski explained that bi- mild end. Dr. Strakowski acknowl- that, when initiating treatment in new- polar disorder and schizophrenia share edged that although this was an inter- onset psychotic patients, they must re- many symptoms (Table 3), thereby esting conceptual model that may be alize that diagnosis is tenuous and will making it difficult to decide in an acute, correct in that there seem to be some have to be reconsidered over time. His- cross-sectional evaluation with which shared genes, it still does not help to torically, an uncertain diagnosis pre- illness the patient is presenting. Both develop treatment strategies. sented the problem of deciding which conditions present with psychosis, par- treatment to use: a mood stabilizer, ticularly in the manic phase of bipolar Making a Diagnosis in Patients such as lithium or divalproex, which is disorder. Attempts to identify types of With New-Onset Psychosis effective for mania but not particularly psychotic symptoms that are specific According to Dr. Strakowski, deter- effective for psychosis, or a conven- for each condition have typically failed, mining a diagnosis of bipolar disorder tional antipsychotic, which is effective especially in multicultural samples. or schizophrenia in patients with a for mania but not particularly effective

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for preventing depressive symptoms what side effect is likely to be most REFERENCES and may even worsen the depression problematic and then match the pa- in bipolar patients. Fortunately, the de- tient with a drug that has a low risk for 1. Kraepelin E. Dementia Præcox and Paraphrenia. Edinburgh, Scotland: velopment of the second-generation that side effect. For example, if a pa- E & S Livingstone: 1919 antipsychotics has helped to solve the tient is overweight, that patient should 2. Fennig S, Kovasznay B, Rich C, et al. problem of how to treat new-onset be treated with a drug that does not Six-month stability of psychiatric diag- noses in first-admission patients with psychosis patients who may have bi- cause weight gain. Similarly, if a psychosis. Am J Psychiatry 1994;151: polar disorder or schizophrenia. In re- young muscular patient may be at high 1200Ð1208 cent years, all second-generation anti- risk for EPS, that patient should be 3. Strakowski SM. Diagnostic validity of schizophreniform disorder. Am J psychotics—risperidone, olanzapine, treated with a drug that has a low pro- Psychiatry 1994;151:815Ð824 quetiapine, ziprasidone, and aripipra- pensity for EPS. 4. Tohen M, Vieta E, Ketter TA, et al. Olanzapine in the treatment of bipolar zole—have been shown to be effec- depression. Arch Gen Psychiatry. tive acute antimanic treatments, thus Acute Versus Long-Term Treatment In press providing a new class of treatment al- Dr. Strakowski offered that the 5. Tohen M, Bowden CL, Calabrese JR, et al. Olanzapine versus placebo for ternatives for managing new-onset treatment used in acute mania or psy- relapse prevention in bipolar disorder. psychosis patients who might have a chosis is not necessarily the treatment In: New Research Abstracts of the 156th manic condition. that will be used long term. In most Annual Meeting of the American Psychi- atric Association; May 19, 2003; San patients with bipolar disorder, the type Francisco, Calif. Abstract NR197:73 Second-Generation Antipsychotics of treatment changes throughout the 6. Jones MW, Huizar K. Quetiapine mono- as Antidepressant and Maintenance course of illness and the demands of therapy for acute mania associated with bipolar disorder (STAMP 1 and STAMP Treatments the illness require a fairly dynamic 2). In: New Research Abstracts of the Dr. Strakowski reported that a sec- and flexible treatment plan. The treat- 156th Annual Meeting of the American ond-generation antipsychotic, olanza- ment goal is to always strive toward Psychiatric Association; May 20, 2003; San Francisco, Calif. Abstract NR432: pine, has been shown to be an effec- a single mood stabilizer, and for 162 tive acute antidepressant in bipolar some patients that may be a second- 7. Bourin M, Auby P, Swanink R, et al. disorder4 as well as an effective main- generation antipsychotic. However, Aripiprazole versus haloperidol for 5 maintained treatment effect in acute tenance agent in bipolar disorder. the reality is that most bipolar patients mania. In: New Research Abstracts These findings are important because will receive some combination of of the 156th Annual Meeting of the American Psychiatric Association; they suggest that the newer antipsy- mood stabilizers, antipsychotics, and, May 20, 2003; San Francisco, Calif. chotics, unlike the conventional anti- perhaps, antidepressants as treatment. Abstract NR467:175 psychotics, may treat and not worsen Similarly, in schizophrenia, clinicians bipolar depression. Dr. Strakowski al- should attempt to strive toward a lowed that this effect could be specific single antipsychotic, but as is the case to olanzapine, but he suspected that with bipolar patients, most schizo- Long-Term Treatment the effect will be found in several of phrenic patients will be treated with of Schizophrenia: Moving the new antipsychotics. They seem to different combinations over time. For- share the ability to treat depressive tunately, a completely expanded treat- From a Relapse-Prevention symptoms in patients with schizophre- ment armamentarium for bipolar dis- Model to a Recovery Model nia, which suggests that they have order is now available, which provides some antidepressant properties. Que- opportunities for novel interventions John M. Kane, M.D., spoke on the tiapine6 and aripiprazole7 demon- that may not have been identifiable long-term treatment of schizophrenia, strated some ability to prevent recur- even a decade ago. focusing specifically on treatment rence of affective illness in 12-week strategies to achieve functional recov- mania trials, suggesting atypical anti- Conclusion ery in patients with schizophrenia. psychotics other than olanzapine may Dr. Strakowski concluded by as- have maintenance capability. serting that clinicians cannot become Functional Recovery as an imprecise diagnosticians because sec- Outcome for Long-Term Treatment Choosing a Second-Generation ond-generation antipsychotics can be Dr. Kane started by stating some of Antipsychotic used to treat bipolar disorder and the challenges in the long-term treat- Because the various second- schizophrenia. Instead, they must rec- ment of schizophrenia: ensuring re- generation antipsychotic drugs have ognize that these are nonspecific treat- sponse of symptoms to treatment, en- been shown to be effective for psy- ments, and if more specific (and ide- suring treatment adherence, and chosis and mania, Dr. Strakowski sug- ally more effective) treatments are to facilitating psychosocial and voca- gested that clinicians may find them- be developed, clinicians have to con- tional functioning. The ultimate out- selves choosing a treatment on the tinue to refine their ability to dis- come of long-term treatment is func- basis of an agent’s side effect profile. tinguish among different psychiatric tional recovery, which is achieved They should identify in a given patient disorders. through the integration of relapse

1384 J Clin Psychiatry 64:11, November 2003 ACADEMIC HIGHLIGHTS prevention with psychosocial and treatment is often a factor in their re- able soon in the United States. Long- vocational therapies. lapse but adherence may be improved acting risperidone was administered Dr. Kane opined that, so far, psy- with second-generation medications. to schizophrenic patients (N = 615) chiatrists have fallen short in terms of An analysis3 of pharmacy refill records during a 12-month trial.5 Three differ- producing ideal levels of functional re- for a 12-month period revealed that ent doses—25 mg, 50 mg, or 75 mg— covery. He cited data from a study1 of the adherence rate was higher in pa- were used, and patients in all dose- patients with first-episode schizophre- tients taking the second-generation groups improved. Total scores on the nia that suggested that the patients had agents risperidone (N = 80), olanza- PANSS improved significantly a relatively low rate of recovery over a pine (N = 63), and quetiapine (N = 28) (p < .01), as did scores on the positive 5-year period, despite participating in than in patients taking the conven- (p < .01) and negative (p < .001) what Dr. Kane considered a well- tional agents haloperidol (N = 57) and factors. staffed research program using state- perphenazine (N = 60). At 6 months, of-the-art treatment, albeit with con- patients taking the second-generation Conclusion ventional antipsychotic drugs. antipsychotics had a significantly Dr. Kane summed up his presenta- (p = .05) higher adherence rate, and tion by suggesting that effective medi- Strategies for Enhancing Recovery although these patients maintained that cation treatment is the enabler that Dr. Kane offered several strategies higher rate at 12 months, the differ- makes the recovery of function pos- for enhancing the likelihood of recov- ence was no longer significant. Even sible. The success of rehabilitation or ery. First, treatment should be im- with second-generation medications, psychosocial treatment is dependant proved through the use of antipsy- adherence is not ideal. In this analysis, upon sound pharmacotherapy. There- chotic medications that are more patients taking second-generation fore, increasing the rates of functional broadly effective and better tolerated, agents went without medication for recovery in schizophrenia is a matter so patients will be more likely to main- approximately 4 days per month. of taking advantage of new develop- tain wellness and adhere to treatment. ments in antipsychotic treatment Next, care should be integrated more Advances in Antipsychotic and ensuring that they are integrated efficiently across patient service de- Treatment for Recovery with other forms of treatment that are livery systems and among providers. Dr. Kane reminded clinicians that, not always readily available to all Finally, communication should be because the second-generation medi- patients, such as psychosocial and improved between clinicians and cations have safety and tolerability vocational therapies. With all these patients, clinicians and other care- advantages over the conventional anti- elements in place, moving from a givers, and clinicians and patients’ psychotics, the likelihood of improv- relapse-prevention model to a recov- families. ing the rate of functional recovery for ery model in schizophrenia treatment Reducing relapse rates. Focusing patients with schizophrenia is possible, is possible. on pharmacotherapy as a recovery assuming clinicians can provide ap- strategy, Dr. Kane pointed to data that propriate medical monitoring and REFERENCES suggest that relapse rates in patients management. 1. Robinson D, Woerner MG, Alvir JM, with schizophrenia may be reduced Dr. Kane echoed others’ hope that et al. Predictors of relapse following with the second-generation antipsy- recent advances with newer-genera- response from a first episode of schizo- 2 phrenia or schizoaffective disorder. chotics. Leucht et al. reviewed 11 tion antipsychotics show promise for Arch Gen Psychiatry 1999;56: studies, with a total of over 2000 pa- facilitating recovery of patients with 241Ð247 tients, on the prevention of schizo- schizophrenia. Aripiprazole has been 2. Leucht S, Barnes TRE, Kissling W, et al. Relapse prevention in schizophrenia with phrenic relapse in patients who were found to be an effective long-term new-generation antipsychotics: a system- treated with newer antipsychotics; the maintenance treatment for schizophre- atic review and exploratory meta-analysis authors concluded that these agents nia.4 In a 52-week multicenter, ran- of randomized-controlled trials. Am J Psychiatry 2003;160:1209Ð1222 may reduce relapse. According to this domized, double-blind trial, patients 3. Dolder CR, Lacro JP, Dunn LB, et al. analysis, compared with conventional (N = 1294) were assigned to treatment Antipsychotic medication adherence: is antipsychotics, second-generation with aripiprazole or haloperidol. More there a difference between typical and atypical agents? Am J Psychiatry agents had statistically significant aripiprazole-treated patients re- 2002;159:103Ð108 lower relapse rates. In terms of treat- sponded and continued treatment than 4. Kujawa M, Saha AR, Ingenito GG, et al. Aripiprazole for long-term maintenance ment failure, 49% of patients treated did haloperidol-treated patients. Nega- treatment of schizophrenia [abstract]. with second-generation antipsychotics tive and depressive symptoms were Int J Neuropsychopharmacol 2002;5 dropped out of the studies early, significantly (p < .03) improved with (suppl 1):S186ÐS187 5. Fleischhacker WW, Eerdekens M, whereas 66% of patients treated with aripiprazole over haloperidol. Karcher K, et al. Treatment of schizophre- conventional agents did so. Another advance is the develop- nia with long-acting injectable risperi- Improving treatment adherence. ment of a long-acting injectable form done: a 12-month evaluation of the first long-acting second-generation antipsy- Dr. Kane reiterated that among patients of risperidone, which is available in chotic. J Clin Psychiatry 2003;64: with schizophrenia, nonadherence to many countries and should be avail- 1250Ð1257

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Figure 2. Rank Order of Side Effects That Elicited Moderate-to-Severe Distress in the patient is likely to continue taking a Study of 99 Outpatients With Stable Schizophrenia Treated With Conventional the drug over the long term. Antipsychotics or Risperidonea In addition to influencing compli- ance, side effects can affect patients’ 50 physical health. Dr. Marder reported that the impact of antipsychotics on 40 physical health is of great concern be-

30 cause patients with schizophrenia al- ready have increased risk for mortality 20 compared with the general population. He referenced a review by Harris and 10 Barraclough,2 which found that indi- atients (%) Who Reported atients (%) P Moderate-to-Severe Distress Moderate-to-Severe viduals with schizophrenia have about

When Experiencing a Side Effect 0 Akinesia Weight Anticholinergic Sexual Muscle Akathisia a 20% shorter life expectancy than the (N = 49) Gain Problems Problems Rigidity (N = 38) (N = 58) (N = 45) (N = 39) (N = 32) general population. Dr. Marder ex- plained that in 2000, the average life aData from Weiden and Miller.1 expectancy was 77 years for the gen- eral U.S. population3 but would have been only 62 years for people with schizophrenia. Although the increased risk for suicide in patients with schizo- Safety and Tolerability of Long-Term Antipsychotic Therapy phrenia contributes to the greater mortality, natural causes such as circu- Stephen R. Marder, M.D., spoke often shaped by the side effects that latory, digestive, respiratory, and geni- about how safety and tolerability of the patient experiences. Therefore, if tourinary diseases add to patients’ antipsychotic therapy can influence patients with schizophrenia tell their risk.2 Dr. Marder added that increased the long-term outcomes of patients clinicians that they like a particular an- risk for developing those diseases is a with schizophrenia. For example, pa- tipsychotic, the reason could be that side effect of some antipsychotics. tients who are unable to tolerate the they like the side effect profile of the side effects of an antipsychotic might drug. Alternatively, if patients dislike Safety and Tolerability discontinue their treatment and expe- an antipsychotic, the reaction could be Profiles of Antipsychotics rience a recurrence of psychotic symp- caused by discomfort related to a side Dr. Marder reported that many anti- toms. Even if patients regularly take effect. psychotics are associated with the an antipsychotic, the benefits on men- To address the value of examining same side effects, but the antipsy- tal health might be outweighed by the patients’ distress in response to side chotics differ in the degree of risk for negative effects on physical health. effects, Dr. Marder cited a study by these adverse effects, including weight To ensure that patients with schizo- Weiden and Miller.1 The authors asked gain, dyslipidemia, elevated prolactin phrenia control their psychotic symp- 99 outpatients with schizophrenia who level, and EPS (Table 4). During his toms without greatly impacting their were stable on first-generation anti- discussion, Dr. Marder provided some physical health, Dr. Marder outlined psychotic or risperidone treatment not specific examples. some common side effects of antipsy- only whether they were experiencing a The risk for weight gain varies chotics, monitoring recommendations, side effect but also how much distress greatly among antipsychotics accord- and the degree to which currently used the side effect caused them. The side ing to a report by Allison and cowork- antipsychotics are associated with effect that was most disturbing to pa- ers.5 The newer-generation antipsy- these side effects. tients during chronic treatment was chotics clozapine and olanzapine and akinesia, followed closely by weight the first-generation antipsychotics Importance of Attending gain, anticholinergic problems, and thioridazine and mesoridazine were as- to Side Effects sexual problems (Figure 2). However, sociated with the greatest weight gains Dr. Marder advised that clinicians some patients felt no or only mild dis- while ziprasidone, fluphenazine, and who prescribe long-term treatment for tress related to a side effect they expe- haloperidol were associated with the patients with schizophrenia must rou- rienced. Weiden and Miller pointed out lowest. Aripiprazole, the newest anti- tinely monitor and control medication that objective physical findings might psychotic, was not included in that side effects to make certain that pa- not correlate with subjective distress. comparison because the drug was not tients continue to take their antipsy- Dr. Marder concluded that by asking available at the time. The results of a chotic and have good physical health. how much a side effect actually upsets recent 26-week randomized double- As Dr. Marder explained, a patient’s individual patients, clinicians will be blind study6 in 310 patients with stable subjective view of an antipsychotic is better able to determine whether or not chronic schizophrenia showed that

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Table 4. Frequency of Side Effects of Newer-Generation Antipsychoticsa Side Effect Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Weight gain ± +++ +++ + + ± Dyslipidemia ± +++ +++ ++ + ± Diabetes mellitus ± +++ +++ + + ± QTc prolongation ± ++ + + + ++ Decrease in orthostatic blood pressure ± +++ + ++ ++ ± Elevated prolactin level ± ±±±+++ ± Extrapyramidal symptoms ± to + ±±to + * ±±to + * ± to + * Tardive dyskinesia ± (?) ±±(?) ± (?) ± to + ± (?) Somnolence ± +++ + ++ ±± aAdapted, with permission, from Jibson and Tandon.4 Symbols: * = dose related; (?) = not clearly established; ± = no to minimal, + = occasional, ++ = frequent, +++ = substantial occurrence of side effect compared with placebo rates. weight gain was comparable for ari- mine subjective distress and also test In general, an electrocardiogram will piprazole and placebo. Another 26- for side effects to determine medica- be unnecessary. However, patients week double-blind trial7 compared tions’ effects on physical health. He taking thioridazine, mesoridazine, or weight changes in 317 patients ran- highlighted recommendations devel- ziprasidone, which can substantially domly assigned to treatment with ari- oped at the Mount Sinai consensus prolong the QTc, should receive an piprazole or olanzapine for acute re- conference.9 electrocardiogram at baseline and lapse of schizophrenia. Patients taking Weight gain/unfavorable body every year after. olanzapine gained a mean weight of 4.2 mass index. Clinicians should be Elevated prolactin level. A marked kg (9.3 lb) while those taking aripipra- aware of their patients’ body mass increase in prolactin level can cause zole lost a mean weight of 1.4 kg (3.1 index (BMI), and patients should be intolerable sexual side effects that lead lb), a significant difference (p < .001). weighed at every clinical visit for the to treatment discontinuation. There- Recent research has also compared first 6 months after therapy with a new fore, clinicians should question pa- the risk for hyperlipidemia among anti- antipsychotic is begun and then every tients about sexual side effects yearly. psychotics. When Lambert et al.8 6 months thereafter. Women should be asked about changes analyzed a Medi-Cal database of 4371 Dyslipidemia. Cholesterol and tri- in menstruation, libido, and unex- patients with schizophrenia, the re- glyceride levels should be checked be- pected lactation. Men should be asked searchers found that clozapine and fore patients begin treatment with a about changes in libido and erectile olanzapine but not quetiapine or risper- new antipsychotic and every year and ejaculatory functioning. idone were associated with a substan- thereafter for most patients, especially Movement disorders. Movement tially greater risk for hyperlipidemia those who gain more than 7% of their disorders such as EPS and tardive dys- than were first-generation antipsy- body weight while taking the medica- kinesia are associated, to some degree, chotics. In the study7 of aripiprazole tion. If abnormal lipid levels are found, with every antipsychotic. Rating scales and olanzapine, hyperlipidemia oc- psychiatrists should ensure that pa- may be useful in identifying these curred more often in the group taking tients with schizophrenia receive stan- conditions. All patients should be olanzapine than in the group taking ari- dard recommended treatment such as monitored for EPS at baseline, at every piprazole. therapy with a cholesterol-lowering visit as long as symptoms are present, Dr. Marder noted that because each drug. and then yearly if symptoms are not antipsychotic has a unique side effect Type 2 diabetes mellitus. Baseline a problem. Symptoms of tardive dys- profile, switching the antipsychotic glucose level should be tested for all kinesia should be assessed at baseline might be a useful intervention for pa- patients before they start a new anti- and every 6 months for patients taking tients who are unable to tolerate an ad- psychotic. For individuals who have a first-generation antipsychotics and verse effect of their current medication. significant risk factor for diabetes, such every year for patients taking a newer- as a gain of more than 7% of their body generation antipsychotic. Monitoring for Side Effects weight or a family history of diabetes,

Compared with the general popula- fasting glucose or hemoglobin A1C Conclusion tion, patients with schizophrenia are, as level should be monitored 4 months Dr. Marder concluded his presenta- a group, at higher risk for conditions after starting an antipsychotic and then tion by saying that to ensure good long- such as hyperlipidemia and type 2 yearly. term outcomes in schizophrenia, the diabetes mellitus. Taking antipsy- Cardiovascular disease. Because clinician must be aware of which an- chotics associated with these illnesses patients with schizophrenia are at high tipsychotic side effects each patient is further raises patients’ risk. Dr. Marder risk for obesity, hyperlipidemia, and experiencing and how the side effects advised that clinicians should always type 2 diabetes mellitus, they are also are impacting the individual’s physical ask patients about side effects to deter- at great risk for cardiovascular disease. health.

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nvsr51_03.pdf. Accessed Sept 30, 2003 versus olanzapine. In: New Research Ab- REFERENCES 4. Jibson MD, Tandon R. New atypical anti- stracts of the 156th Annual Meeting of the psychotic medications. J Psychiatr Res American Psychiatric Association; May 19, 1. Weiden PJ, Miller AL. Which side effects 1998;32:215Ð228 2003; San Francisco, Calif. Abstract really matter? screening for common and 5. Allison DB, Mentore JL, Moonseong H, NR231:86 distressing side effects of antipsychotic et al. Antipsychotic-induced weight gain: 8. Lambert B, Tafesse E, Carson WH. medications. J Psychiatr Pract 2001;7: a comprehensive research synthesis. Antipsychotic-induced hyperlipidemia 41Ð47 Am J Psychiatry 1999;156:1686Ð1696 among people with schizophrenia. In: New 2. Harris EC, Barraclough B. Excess mortal- 6. Carson WH, Pigott TA, Saha AR, et al. Research Abstracts of the 156th Annual ity of mental disorder. Br J Psychiatry Aripiprazole vs. placebo in the treatment of Meeting of the American Psychiatric Asso- 1998;173:11Ð53 chronic schizophrenia [poster]. Presented ciation; May 21, 2003; San Francisco, 3. Aria E. United States Life Tables, 2000. at the 42nd annual meeting of the New Calif. Abstract NR569:213 National Vital Statistics Reports, vol 51, Clinical Drug Evaluation Unit; June 10Ð13, 9. Marder SR, Essock SM, Miller AL, et al. no. 3. Hyattsville, Md: National Center for 2002; Boca Raton, Fla The Mount Sinai conference on the phar- Health Statistics; 2002. Available at: http:// 7. McQuade RD, Jody D, Kujawa MJ, et al. macotherapy of schizophrenia. Schizophr www.cdc.gov/nchs/data/nvsr/nvsr51/ Long-term weight effects of aripiprazole Bull 2002;28:5Ð16

Newer-Generation Antipsychotics for the Management of Psychosis in Older Patients With Dementia J. Michael Ryan, M.D., spoke about tions because older patients are often had, on average, more than 3 medical the prevalence of neuropsychiatric more frail and susceptible to adverse conditions. More than 20% of the symptoms in older patients with de- effects such as cardiovascular and subjects were taking 10 or more mentia and psychosis. He addressed metabolic complications, anticholin- medications. considerations for using antipsychotic ergic effects, EPS, tardive dyskinesia, therapy in this special population, in- and sedation than are younger patients. Safety of Newer-Generation cluding the efficacy and safety of treat- Dr. Ryan explained the potential con- Antipsychotics in Older Patients ment with some newer-generation anti- sequences of some adverse effects. With Dementia psychotics for these patients. EPS and tardive dyskinesia can result A growing body of literature has in poor coordination, disfigurement, shown that newer-generation antipsy- Prevalence of Neuropsychiatric social isolation, and falls that might chotics effectively reduce psychotic Symptoms in Older Patients cause lethal injuries in older patients. symptoms without dangerous side ef- With Dementia Sedation may interfere with activities fects in older patients with dementia. Dr. Ryan noted that until Lyketsos of daily living, and anticholinergic ef- Dr. Ryan highlighted some of the out- et al.1 published a population-based fects may worsen confusion and comes from controlled clinical trials of study in 2000, little was known about memory impairment in patients with risperidone, olanzapine, quetiapine, the prevalence of neuropsychiatric dementia. and aripiprazole. symptoms in community-dwelling Comorbid medical disorders and Risperidone. Katz et al.3 conducted older patients with dementia. Lyketsos concomitant medications also influ- a 12-week double-blind, placebo- and colleagues identified neuropsychi- ence antipsychotic choice. In a study2 controlled trial of risperidone in 625 atric symptoms in 1002 patients aged of almost 300,000 older nursing home patients aged 55 years or older who 65 years or older using the Neuro- residents in 5 U.S. states, participants had dementia and lived in a nursing psychiatric Inventory (Table 5). The 1-month prevalence of any neuro- psychiatric symptom in participants Table 5. Frequency of Neuropsychiatric Inventory Item Domains in with dementia was 60%. About 19% 1002 Participants With or Without Dementia in a Community Study of the subjects with dementia had delu- of People Aged 65 Years or Older in Cache County, Utaha sions, and about 14% experienced With Dementia Without Dementia hallucinations. (N = 329) (N = 673) Item Domain N % N % Special Considerations for the Apathy 90 27.4 21 3.1 Antipsychotic Management of Depression 78 23.7 47 7.0 Agitation/aggression 78 23.7 19 2.8 Older Patients With Dementia Irritability 67 20.4 30 4.5 According to Dr. Ryan, clinicians Delusions 61 18.5 16 2.4 must consider the special characteris- Anxiety 56 17.0 38 5.6 tics of older patients with dementia Hallucinations 45 13.7 4 0.6 Aberrant motor behavior 47 14.3 3 0.4 when choosing an antipsychotic. Disinhibition 30 9.1 6 0.9 Antipsychotic choice often depends Elation 3 0.9 2 0.3 on the side effect profiles of medica- aAdapted with permission from Lyketsos et al.1 Data for some patients are missing for some domains.

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home or in a hospital for patients with in the quetiapine group and 2 mg/day Figure 3. Mean Change From chronic diseases. Compared with pa- in the haloperidol group. All patients Baseline in BPRS Total Score tients who took placebo, more patients with Alzheimer’s disease had substan- in 195 Patients Aged 55 Years or treated with 1 or 2 mg/day of risperi- tial improvement in total Brief Psychi- Older With Alzheimer’s Disease done experienced ≥ 50% improvement atric Rating Scale (BPRS) scores but Randomly Assigned to Treatment a in total Behavioral Pathology in Alz- not psychotic symptoms, regardless of With Aripiprazole or Placebo (LOCF) heimer’s Disease rating scale scores. treatment. Treatment with quetiapine Week 6 Week 10 The side effect profile of the 3 doses of and haloperidol did, however, reduce 0 risperidone (0.5, 1.0, and 2.0 mg/day) agitation significantly more than pla- –2 was generally good, but dose-related cebo did. Improvement in functioning increases were seen in the rates of some was significantly greater with quetia- –4 adverse events such as somnolence and pine than haloperidol. In general, the EPS. Interestingly, the incidence of side effect profile of quetiapine was –6 Mean Change in falls was lower in the groups of pa- favorable. Compared with patients Score BPRS Total –8 tients who took 0.5 or 1.0 mg/day (but who took placebo or haloperidol, fewer * not 2.0 mg/day) of risperidone than in patients treated with quetiapine had –10 Placebo (N = 95) the group who took placebo. Whether EPS, falls, or fractures. Anticholiner- Aripiprazole (N = 100) treating psychosis in dementia with an gic effects were more prevalent in the aAdapted from De Deyn et al.6 Baseline BPRS appropriate dose of an antipsychotic placebo group than in the quetiapine total scores were 43.42 in the placebo group and 43.63 in the aripiprazole group. may reduce older patients’ risk of falls and haloperidol groups, but somno- *p = .045 vs. placebo. is currently being investigated. lence occurred more often in the active Abbreviations: BPRS = Brief Psychiatric Rating Olanzapine. In a 6-week, random- treatment groups. Scale, LOCF = last observation carried forward. ized, double-blind trial, Street and co- Aripiprazole. Aripiprazole, at flex- workers4 compared the efficacy and ible doses of 2 to 15 mg/day, was re- safety of olanzapine and placebo in cently compared with placebo in a 10- occurred during the trial, 5 with pla- reducing psychotic symptoms in 206 week, randomized trial conducted by cebo and 8 with aripiprazole. subjects who ranged in age from 61 to De Deyn et al.6 The 208 community- Future research. The National In- 94 years, had Alzheimer’s disease, and dwelling patients, who had a mean age stitute of Mental Health and the Uni- lived in a nursing home. The primary of 82 years, had been diagnosed with versity of North Carolina at Chapel outcome measure was change from Alzheimer’s disease and psychosis. Hill7 are currently recruiting patients baseline to endpoint in Core Total The mean dose of aripiprazole at end- for an effectiveness study that will (Agitation/Aggression, Hallucinations, point was 10 mg/day. The change from compare newer-generation antipsy- and Delusions items) scores on the baseline to endpoint in the Neuropsy- chotics in the management of outpa- Neuropsychiatric InventoryÐNursing chiatric Inventory Hallucinations and tients with Alzheimer’s disease and Home version. According to this crite- Delusions Subscale score was not sig- clinically significant psychosis or rion, patients treated with 5 mg/day of nificantly greater for the aripiprazole agitation. olanzapine experienced greater im- group than for the placebo group. How- provement (Ð7.6 change) than patients ever, the aripiprazole group had sig- Conclusion who received 10 mg/day (Ð6.1) or 15 nificantly greater decreases in total Dr. Ryan noted that managing older mg/day (Ð4.9) of olanzapine and those BPRS score at week 6 (Figure 3) as patients with dementia and neuropsy- who took placebo (Ð3.7). The only ad- well as BPRS Core Subscale and BPRS chiatric symptoms using the newer- verse events that occurred significantly Psychosis Subscale scores at study generation antipsychotics can be ef- (p < .05) more often in any olanzapine endpoint. There were no side effects fective and safe when a medication groups than in the placebo group were occurring at an incidence of greater with a favorable side effect profile is somnolence (a dose-related risk 4.9 to than or equal to 10% in the aripipra- chosen and given at an appropriate 8.2 times higher with olanzapine) and zole group. The only side effect that dose. abnormal gait (7.5 to 11.2 times higher occurred at least 5% more often in the risk with olanzapine). aripiprazole than the placebo group REFERENCES Quetiapine. Tariot et al.5 conducted was somnolence (8% versus 1%). 1. Lyketsos CG, Steinberg M, Tschanz JT, et subanalyses for 284 subjects with Alz- Somnolence was not associated with al. Mental and behavioral disturbances in heimer’s disease who participated in a falls and no patients discontinued treat- dementia: findings from the Cache County 10-week, randomized, double-blind, ment due to somnolence. The inci- Study on Memory in Aging. Am J Psychia- try 2000;157:708Ð714 placebo-controlled, flexible-dosing dence of EPS was similar in the 2 2. Bernabei R, Gambassi G, Lapane K, et al. trial of quetiapine and haloperidol in groups as assessed by the Simpson- Characteristics of the SAGE database: a 378 older nursing home patients with Angus Scale, the Barnes Akathisia new resource for research on outcomes in long-term care. J Gerontol A Biol Sci Med dementia and psychotic symptoms. Scale, and the Abnormal Involuntary Sci 1999;54:M25ÐM33 The mean daily dose was 120 mg/day Movement Scale. A total of 13 falls 3. Katz IR, Jeste DV, Mintzer JE, et al.

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Comparison of risperidone and placebo and others), haloperidol (Haldol and others), honoraria from and is a member of the for psychosis and behavioral disturbances mesoridazine (Serentil), olanzapine (Zyprexa), speakers/advisory boards for Johnson & associated with dementia: a randomized, perphenazine (Trilafon and others), quetiapine Johnson, Eli Lilly, Bristol-Myers Squibb, Otsuka, double-blind trial. J Clin Psychiatry (Seroquel), risperidone (Risperdal), ziprasidone AstraZeneca, Sanofi-Synthelabo, Fujisawa 1999;60:107Ð115 (Geodon). Pharmaceutical Co., and Pfizer. Dr. Kane is a 4. Street JS, Clark WS, Gannon KS, et al. consultant for Abbott, Aventis, Bristol-Myers Olanzapine treatment of psychotic and be- Disclosure of off-label usage Squibb, Organon, Novartis, Janssen, Eli Lilly, havioral symptoms in patients with Alzhei- Dr. Strakowski has determined that, to the best and Pfizer. Dr. Marder is a consultant for mer disease in nursing care facilities. Arch of his knowledge, aripiprazole, quetiapine, and Bristol-Myers Squibb, Janssen, and Eli Lilly; is Gen Psychiatry 2000;57:968Ð976 risperidone are not approved by the U.S. Food a member of the speakers/advisory boards for 5. Tariot P, Schneider L, Katz IR, et al. Que- and Drug Administration for the treatment of and has received research/grant support and tiapine in nursing home residents with Alz- mania. If you have questions, contact the medical honoraria from Bristol-Myers Squibb, Janssen, heimer’s dementia and psychosis [poster]. affairs department of the manufacturer for the Eli Lilly, AstraZeneca, and Pfizer. Dr. Ryan is a Presented at the 15th annual meeting of the most recent prescribing information. consultant for Bristol-Myers Squibb; has American Association for Geriatric Psychi- received research/grant support from the atry; Feb 24Ð27, 2002; Orlando, Fla National Institutes of Health, National Institute 6. De Deyn P, Jeste D, Auby P, et al. Ari- Financial disclosure of Mental Health, Janssen, and Mitsubishi piprazole for psychosis of Alzheimer’s dis- In the spirit of full disclosure and in Pharma; and is on the speakers/advisory ease [poster]. Presented at the 16th annual compliance with all ACCME Essential Areas boards for Abbott, Pfizer-Eisai, AstraZeneca, meeting of the American Association for and Policies, the faculty for this CME activity Janssen, Bristol-Myers Squibb, and Forest. Geriatric Psychiatry; March 1Ð4, 2003; were asked to complete a full disclosure Dr. Strakowski is a consultant for Ortho- Honolulu, Hawaii statement. Dr. Weiden has received research/ McNeil, Bristol-Myers Squibb, Otsuka, 7. Clinical Antipsychotic Trials in Interven- grant support and honoraria from and is a AstraZeneca, and Eli Lilly; has received tion Effectiveness (CATIE): Alzheimer’s consultant and member of the speakers/advisory research/grant support from Bristol-Myers Disease Study. Available at: http:// boards for AstraZeneca, Bristol-Myers Squibb, Squibb, Otsuka, AstraZeneca, Eli Lilly, and www.catie.unc.edu/alzheimers/about.html. Janssen, and Pfizer. Dr. Fleischhacker is a Janssen; and has received honoraria from and Accessed October 2, 2003 consultant for Johnson & Johnson; has received is a member of the speakers/advisory boards for research/grant support from Eli Lilly, Sanofi- Bristol-Myers Squibb, Otsuka, AstraZeneca, Drug names Synthelabo, and Servier; and has received Eli Lilly, Janssen, and Ortho-McNeil. aripiprazole (Abilify), chlorpromazine (Sonazine, Thorazine, and others), clozapine (Clozaril and others), diazepam (Diastat, Valium, and others), To cite a section from this ACADEMIC HIGHLIGHTS, follow the format below: divalproex (Depakote), droperidol (Inapsine Ryan JM. Newer-generation antipsychotics for the management of psychosis in older patients with and others), estrogen (Cenestin, Premarin, dementia, pp 1388Ð1390. In: Weiden PJ, chair. New Developments in Antipsychotic Therapy and others), fluphenazine (Permitil, Prolixin, [ACADEMIC HIGHLIGHTS]. J Clin Psychiatry 2003;64:1379Ð1390

For the CME Posttest for this article, see pages 1400–1402.

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