Journal of Psychiatric Research 35 (2001) 187191 www.elsevier.

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Short communication

Treatment with atypical antipsychotics: new indications and new populations

$

Ira D. Glicka,*, Stephen R. Murrayb, Priya Vasudevanc, Stephen R. Marderd, Rona J. Hue
a

Professor of Psychiatry, Stanford University School of Medicine, 401 Quarry Road, Suite No. 2122, Stanford, CA 94305, USA b Associate Medical Director, Janssen Pharmaceutica, USA c Research Assistant, Stanford University School of Medicine, Stanford, CA, USA d Professor of Psychiatry, School of Medicine, University of California, Los Angeles, CA, USA e Assistant Professor of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA Received 12 November 2000; received in revised form 26 April 2001; accepted 1 May 2001

Abstract Atypical antipsychotics have revolutionized the treatment of schizophrenia, becoming the treatment of choice for patients not only during their rst episode, but also throughout their life course. Of note, as of 1999 more than 70% of prescriptions for these drugs are being prescribed for conditions other than schizophrenia, such as bipolar disorder and geriatric agitation. While there have been very few controlled trials that have established the ecacy of the atypical antipsychotics for these o-label uses, there have been a large number of open trials and case reports. The few controlled trials suggest that the atypical antipsychotics may be useful for aective disorders (both mania and depression), geriatric conditions such as senile dementia and aggression, as well as a variety of other disorders. Atypical agents may be particularly helpful for elderly, child, or adolescent patients who are especially susceptible to the side eects of medications and whose risk of tardive dyskinesia is high but further controlled studies are necessary. # 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Mood Disorders; Dementia; Pervasive Developmental Disorder; OCD; Schizophrenia; Atypical Antipsychotics

Antipsychotic medications are being used for nearly every medical and psychiatric condition that include psychosis as a symptom. Indications for antipsychotics, since the 1950s, have included acute schizophrenia and schizoaective disorders, manic episodes in bipolar aective disorder, major depressive episodes with psychosis, psychotic disorders due to acute substance use, medical condition (e.g. neoplasm), Huntingtons disease, dementia, pervasive developmental disorder, mental retardation, Tourettes syndrome and borderline personality disorder. Over the last decade, the new generation of atypical antipsychotics are rapidly becoming treatments of choice for schizophrenia
$ Presented in part at the 1999 Biannual Conference of the International Society for Schizophrenia Research, Santa Fe, New Mexico, April 1999 and at the 2000th Annual Meeting of the American Psychiatric Association, Chicago, May 2000. * Corresponding author. Tel.: +1-650-723-3519; fax: +1-650-7232507. E-mail address: iraglick@stanford.edu (I.D. Glick).

and are gradually beginning to be used for other conditions as well. In fact, over 70% of atypical prescriptions are for conditions other than schizophrenia (Buckley et al., 1999). In clinical practice, target symptoms include aggression, suicidality and substance abuse (Buckley et al., 1999). Their advantages over conventional antipsychotics or neuroleptics include a generally better side eect prole, with fewer extrapyramidal symptoms and a lower risk of tardive dyskinesia. They may, in addition, improve negative symptoms and certain parameters of cognition. New, atypical antipsychotics currently approved (as of January 2000) by the US Food and Drug Administration for the treatment of schizophrenia include risperidone, olanzapine and quetiapine, which, having become the rst-line treatments for schizophrenia, are now being used for o-label indications. In this review we present a detailed summary of the data regarding olabel indications (both symptoms and disorders) for these drugs, including all the randomized controlled

0022-3956/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0022-3956(01)00020-6

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studies that we were able to locate, and many other published reports. Clozapine, approved for patients with treatment-resistant schizophrenia since 1989, will not be considered here, because its most serious potential side eect, agranulocytosis, has limited its o-label use. Because atypical antipsychotics are already being used for o-label indications, the major issue we wish to address is the evidence for their ecacy. It would be useful to compare ecacy of atypicals to the rst-generation conventional antipsychotics, but there is a lack of head-to-head comparisons between them. And it is unlikely that such studies will be done.

Methodology We have done a Medline search for reports on risperidone, olanzapine and quetiapine for conditions other than schizophrenia. We included all published controlled and non-controlled studies in peer-reviewed journals. Our purpose was to do an inclusive summary. We then cross-checked with the manufacturers of each of these medications to ensure that there were no omissions. We have not included papers, abstracts or posters presented at meetings, instead choosing peer reviewed publication as of the end of 1999. The number of pub-

Table 1 Summary of open and controlled studies for risperidone, olanzapine and quetiapine by indication other than for schizophreniaa Indication Risperidone Open Psychosis associated with Childhood condition Geriatric condition Huntingtons disease Dementia Depression Medical conditions HIV Substance use Parkinsons disease Movement disorders Tardive dyskinesia Tremor Tardive akathsia Hemichorea PANDAS Tic disorders Respiratory dyskinesia Segmental dystonia Bipolar disorder Pervasive develop-mental disorders Borderline personality disorder Tourettes syndrome Trichotillomia Obsessive-compulsive disorder Depression Lesch-Nyhan disorder Substance abuse PTSD Delusional disorder Delirium Stuttering Brain injury Conduct disorder Pedophilia Mood disorders Total
a

Olanzapine Controlled Open 2 2 1 1 3 3 1 8 Controlled

Quetiapine Open 1 1 Controlled

4 3 10 2 3 4 3 3

1 1 1 1 14 17 2 5 1 12 3 1 2 3 6 2 3 1 1 1 2

4 2 1 1

12 3 1 1 1 5

2 1

2 1

1 119 6 56 3 8 0

Complete references and succinct summary of the studies available from the authors.

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lications correlates with the number of years a medication has been on the market: risperidone, approved in December 1993 was the subject of 120 articles in our review, olanzapine, approved in 1996 had 56 articles and quetiapine, approved in 1997, had l8. Thus, this is a survey of current, peer-reviewed literature. It is not a detailed, critical evaluation or a metaanalysis of the studies both the amount and the quality of the data do not support such a report. Instead, we characterized outcome results as positive or negative, thus oversimplifying the operational criteria for the studies which were included. Our aim was to make the paper readable since the data didnt warrant it to be encyclopedic. And of course, in those very few studies where there were no dierences reported between two treatments, it might have been due to the lack of statistical power due to a small sample size.

movement disorders, bipolar disorder, pervasive developmental disorders, borderline personality disorder, Tourettes Syndrome, trichotillomania, obsessive-compulsive disorder, delirium, clozapine discontinuation syndrome, stuttering and mood disorders. Controlled studies have looked at bipolar disorder in the acute phase and substance-induced psychosis. All of the three controlled studies report positive results (Berk et al., 1999a; Berk et al., 1999b; Tohen et al., 1999) although the Berk study with cannabis induced psychosis refers only to less side eects, on olanzapine, not greater ecacy. There are eight published reports in quetiapines use in non-schizophrenia indications, and all are uncontrolled. The indications include psychosis associated with various medical illnesses, bipolar disorder, and pervasive developmental disorder.

Commentary Results We present a current (as of January 2000) table of reports organized by disease or disorder in both controlled (i.e. randomized, double-blind with a comparison group or a placebo-control) and open-label studies (Table 1). This table is presented to show both the variety of conditions atypicals are being tried for, as well as the nature of the data (controlled vs. uncontrolled). A detailed summary of each controlled study is presented in Table 2. For risperidone, indications other than schizophrenia have been reported in over 119 articles. These include psychotic symptoms associated with a variety of diseases, various movement disorders, bipolar disorder, pervasive developmental disorders, stuttering, borderline personality disorder, brain injury, conduct disorder, delirium, delusional disorder, depression, Lesch-Nyhan disorder, obsessive-compulsive disorder, pedophilia, PTSD, substance abuse, Tourettes syndrome and trichotillomania. Of the six controlled studies, all report positive results, that is, there was suggestive (certainly not denitive) evidence that it helped the condition it was being tested for. The conditions include bipolar disorder as well as behavioral and psychotic symptoms of dementia, pervasive developmental disorders and stuttering (Vanden Borre et al., 1993; McDougle et al., 1998; Muller-Siecheneder et al., 1998; Segal et al., 1998; DeDeyn et al., 1999; Katz et al., 1999; Maguire et al., 1999). However, the bipolar and psychotic depression studies were the only ones in which risperidone was compared to a conventional; the other ve were compared to placebo. Uses for olanzapine have been investigated in both open and controlled studies, of which 56 have been published. The indications studied include psychotic symptoms associated with a variety of diseases, various The atypical antipsychotics have been found to be ecacious for the treatment of schizophrenia, but this review has found that they also are being used for other medical and psychiatric illnesses where aggression or psychosis is the predominant feature. They have been found useful in special populations where side eects are of particular concern: in the elderly and in children and adolescents. The data does not allow a judgment on the relative ecacy among the new drugs or of atypicals compared to conventionals given the lack of head-to-head studies. On the other hand, Buckley et al. (1999) has also found that there are (at least) three issues that serve as barriers to use of atypicals. They cluster into three broad groups: they include (1) side eects (e.g. weight gain, hyperglycemia, sedation, etc.); (2) ecacy/formulation (uncertainty as to dosing, e.g. quetiapine, upper limit on olanzapine dose, lack of data on longterm use, lack of I.M. prep duration); and nally (3) cost/access, i.e. the increased cost compared to conventionals, and who can aord them. There are a number of caveats to the interpretation of these data. First, there is a paucity of controlled data, i.e. very few studies with mostly small sample sizes. We have most condence in the data from randomized controlled trials open reports are (at best) suggestive. Second, the vast majority of published reports are positive, in part, because of the publication bias associated with the use of new drugs in any eld of medicine (Begg and Berlin, 1989). Third, at this juncture there have been no comparisons of data coming from industrysupported studies compared to data which is not supported by industry (e.g. NIMH trials). Having said that, we made a rough, evaluation of outcome of the uncontrolled studies (listed in Table 1) into positive, negative or equivocal/or unknown outcomes.

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Table 2 Summary of ndings of controlled studies of atypicals Drug Risperidone Disorder Dementia Comparator Placebo Findings 344 patients mean age 82 treated for 12 weeks. Risperidone (mean 1.1 mg) mg signicantly better than placebo as measured by clinical improvement and the BEHAVE-AD. 625 patients, mean age 82.7, enrolled and 70% completed. Randomly assigned to placebo or 3 doses of risperidone (0.5, 1 or 2 mgs) treated for 12 weeks. The two higher doses of risperidone showed signicant decreases in symptoms and BEHAVE-AD total scores. A total of 21 patients aged 2074 were randomly assigned for 6 weeks with up to 2 mg risperidone or placebo. Risperidone-treated patients improved on severity but not duration of stuttering. 31 adult patients, mean age 28, were randomly assigned to risperidone (16 mg) or placebo for 12 weeks. 8 out of 14 risperidone patients responded vs. 0/16 placebo-treated patients. 45 patients aged 1958 were randomly assigned to lithium (8001200 mg), risperidone (6 mg) or haloperidol (10 mg) for 28 days. All three groups showed similar improvement. 123 patients aged 1865 were randomly assigned to risperidone (69 mg) or haloperidol/ amitriptyline (6/180 mg) for 6 weeks. The combination of haloperidol and amitriptyline was more eective than risperidone in treating the psychotic and melancholic symptoms. 30 out of 37 patients aged 1565 completed a 3-week add-on trial of risperidone (412 mg). Signicant improvement in Aberrant Behavior Checklist and CGI was demonstrated. 30 pts aged 1865, double-blinded olanzapine (10 mg) vs lithium (400 mg ID) treated for 4 weeks. No dierences in BPRS, CGI or Mania Scale ratings. Olanzapine was signicantly better than lithium on the CGIS at week 4. 30 patients aged 1865 randomly assigned to olanzapine (10 mg) or haloperidol (10 mg) in a 4-week trial. There was no dierence between the arms on BPRS, CGIS, CGII. Haloperidol patients experienced more EPS side eects. 139 pts aged 1865 treated with olanzapine (10 mg) vs. placebo in a 3-week, parallel group design. Olanzapine was statistically better than placebo on the YMRS. EPS side eects did not dier between the groups. Result Positive Sponsor Industry Reference A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. De Deyn, et al., 1999. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. Katz et al., 1999. Stuttering: neuropsychiatric features measured by content analysis of speech and the eect of risperidone on stuttering severity. Maguire et al., 1999. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. McDougle et al., 1998. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Segal et al., 1998. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. Muller-Siecheneder et al., 1998. Risperidone as add-on therapy in behavioural disturbances in mental retardation: a doubleblind placebo-controlled cross-over study. Vanden Borre et al., 1993. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Berk et al., 1999b. A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Berk et al., 1999a. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Tohen et al., 1999.

Risperidone

Dementia

Placebo

Positive

Industry

I.D. Glick et al. / Journal of Psychiatric Research 35 (2001) 187191

Risperidone

Stuttering

Placebo

Positive

Industry

Risperidone

Pervasive developmental disorder BipolarMania

Placebo

Positive

Industry

Risperidone

Haloperidol

Positive

Industry

Risperidone

Psychotic Depression

Haloperidol/ amitriptyline

Negative

Industry

Risperidone

Pervasive developmental disorder Bipolar

Placebo

Positive

Industry

Olanzapine

Lithium

Positive

Industry

Olanzapine

Substanceinduced psychosis Bipolar

Haloperidol

Positive

Industry

Olanzapine

Placebo

Positive

Industry

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Approximately two-thirds were positive, one-ninth negative and one-eighth being equivocal or negative. Of note, there is one uncontrolled study with risperidone, and two studies with olanzapine, suggesting worsening symptoms of obsessive compulsive disorder (al-Mulhim et al, 1998; Andrade, 1998; Morrison et al, 1998). Overall, where atypical antipsychotics are being used for o-label indications, the limited data suggest that these medications can be useful. Some unanswered questions, however, are what their ecacy is, with what side eects, and at what cost. The new atypicals are changing the prescribing practices of psychiatrists in the USA. Buckley et al. (1999) have reported data from both general and specialized psychiatrists in two US states. Respondents reported experience with atypicals in dementia (80% of respondents), autism (40%), developmental delay/mental retardation (65%) and even personality disorders (69%), especially those that show psychotic symptoms like borderline disorder. Therefore, as happened with the conventional antipsychotics, disorders other than schizophrenia are increasingly being treated by atypical antispychotics. Further controlled research is necessary to develop the data to support indications and contraindications for atypical antipsychotics in a variety of populations To develop dierential indications for each drug, blinded head-to-head studies directly comparing the new antipsychotics to each other (and the conventionals) are badly needed.

berg PLJ, Eriksson S. A randomized trial of risperidone, placebo, and haloperidole for behavioral symptoms of dementia. Neurology 1999;53:94655. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, doubleblind trial. J Clinical Psychiatry 1999;60:10715. Maguire GA, Gottschalk LA, Riley GD, Franklin DL, Bechtel RJ, Ashurst J. Stuttering: neuropsychiatric features measured by content analysis of speech and the eect of risperidone on stuttering severity. Comprehensive Psychiatry 1999;40:30814. McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Archives General Psychiatry 1998;55:63341. Morrison D, Clark D, Goldfarb E, McCoy L. Worsening of obsessivecompulsive symptoms following treatment with olanzapine. American J Psychiatry 1998;155:855. Muller-Siecheneder F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depresive syndrome. J Clin Psychopharmacology 1998;18:11120. Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidole in mania: a double-blind randomized controlled trial. Clinical Neuropharmacology 1998;21:17680. Tohen M, Anger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG. Olanzapine versus placebo in the treatment of acute mania. American J Psychiatry 1999;156:7029. Vanden Borre R, Vermote R, Buttie ns M, Thiry P, Dierick G, Geutjens J. Risperidone as add-on therapy in behavioral disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatrica Scandinavia 1993;87:16771.

Addendum References
al-Mulhim A, Atwal S, Coupland NJ. Provocation of obsessive-compulsive behavior and tremor by olanzapine. Can J Psychiatry 1998;43:645. Andrade C. Risperidone may worsen uoxetine-treated OCD. J Clinical Psychiatry 1998;59:2556. Begg CB, Berlin JA. Publication bias and the dissemination of clinical research. J National Cancer Institute 1989;81:10715. Berk M, Brook S, Trandar AI. A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorders: a double-blind randomized controlled trial. International Clinical Psychopharmacology 1999a;14:17780. Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. International Clinical Psychopharmacology 1999b;14:33943. Buckley PF, Miller DD, Singer B, Donenwirth K. Whats new with the new antipsychotics? Presented at the Annual Meeting of the American College of Neuropsychopharmacology; 1999 December; Acapulco, Mexico. De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzen-

Since this paper was accepted, two more randomized, double-blind, contolled studies have come to our attention. (1) Tohen et al. reported greater ecacy of olanzapine than placebo in the treatment of acute bipolar mania and was generally tolerated (over four weeks), and (2) Findling et al. reported that risperidone may have ecacy in the treatment of youth conduct disorder (over 10 weeks).

References
Tohen T, Jacobs TG, Grundy SL, et al. Ecacy of olanzapine in acute bipolar mania. Arch. Gen. Psychiatry September 2000; 57:8419. Findling RL, McNamara NK, Branicky; LA, et al. A double-blind pilot study of risperidone in the treatment of conduct disorder. J. Am. Acad. Child Adolesc. Psychiatry April 2000; 39:50916.