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Antipsychotics for patients without psychosis?
Controlled clinical trial results can help you make two prescribing decisions:
- Is an antipsychotic the right choice for this patient?
- If yes, which agent?
Prescribing antipsychotics off-label can be worthwhile when a patient gets better, but even then two worries remain:
- Most uses of antipsychotics for nonpsychotic illness are not evidence-based.
- This practice may expose clinicians to liability if the patient gets worse.
Consider the use of second-generation antipsychotics (SGAs) to manage acute behaviors in patients with dementia. The FDA ordered a black box warning in 2005 that SGAs may increase mortality risk in older patients. In October, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) reported that SGAs’ side effects offset their benefits when compared with placebo (see Will CATIE-AD change dementia treatment?).1
What do you do when FDA-approved drugs fail to help your patient with dementia, unipolar depression, anxiety disorders, or other nonpsychotic symptoms, and SGAs may be the next consideration? The answers lie in managing side effects and knowing which antipsychotic uses are supported by data from controlled clinical trials, which we review here.
- FGAs showed efficacy for nonpsychotic disorders
- SGAs are associated with a lower risk of EPS and tardive dyskinesia at therapeutic dosages, compared with FGAs
- Many patients fail to respond adequately to medications approved for their illnesses
- Evidence on SGAs’ efficacy in nonpsychotic disorders has grown substantially in the past 10 years.
EPS: extrapyramidal symptoms
FGA: first-generation antipsychotic
SGA: second-generation antipsychotic
Prescribing considerations
For a variety of reasons (Box 1), SGAs have rapidly assumed a major role in treating nonpsychotic disorders. Thirty-one percent of psychotropics are dispensed off-label,2 and Buckley3 reported in a 3-state survey that 70% of SGA prescriptions were written for indications other than schizophrenia.
Using antipsychotics for nonpsychotic symptoms is a longstanding clinical practice. In schizophrenia patients, antipsychotics have been shown to improve psychotic and nonpsychotic symptoms: agitation, violence, negative symptoms, social isolation, depression, suicidality, anxiety, insomnia, poor appetite, compulsions, cognition, smoking, alcohol and drug use, polydipsia, tardive dyskinesia, and tardive dystonia. Some clinicians may view these reports as evidence that antipsychotics might relieve these symptoms in patients with nonpsychotic disorders as well, but the issue is more complicated than that (Box 2).4
Caveats. SGAs do offer clinicians unique tools; no other class of psychotropics can claim efficacy in psychotic disorders, bipolar disorder, depression, and other disorders we describe in this review. On the other hand:
- Although some SGAs are approved for bipolar disorder and one was recently approved to treat irritability in autism (Table 1), most SGA uses in nonpsychotic disorders are off-label and supported by few—if any—large, randomized, controlled trials.
- Antipsychotics can cause the very symptoms they relieve, including depression, obsessive-compulsive disorder (OCD), anxiety, poorer cognition, agitation, mania, insomnia, and abnormal movements.
- Few controlled studies have compared SGAs to usual first-line treatments; most have evaluated SGAs as adjuncts to other psychotropics—such as serotonin reuptake inhibitors (SRIs)—for patients with treatment-resistant disorders.
- Published head-to-head studies have rarely compared the efficacy of various SGAs in treating nonpsychotic disorders.
- Long-term safety studies of SGAs for nonpsychotic indications have not been done.
Table 1
Bipolar and other nonpsychotic indications FDA-approved for SGAs
| SGA | Bipolar mania | Bipolar depression | Bipolar maintenance | Other |
|---|---|---|---|---|
| Aripiprazole | Acute mania or mixed episodes | Bipolar I disorder, most recent episode manic or mixed | ||
| Clozapine | Risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders | |||
| Olanzapine | Acute mania or mixed episodes; monotherapy or with lithium or valproate for manic episodes | Bipolar disorder maintenance monotherapy | ||
| Olanzapine/fluoxetine combination | Bipolar depressive episodes | |||
| Quetiapine | Acute manic episodes; monotherapy or with lithium or valproate | Bipolar depressive episodes | ||
| Risperidone | Acute mania or mixed episodes; monotherapy or with lithium or valproate | Irritability in autism | ||
| Ziprasidone | Acute manic or mixed episodes | |||
| SGA: second-generation antipsychotic (oral forms) | ||||
Prescribing decisions. SGA’s potential adverse effects complicate clinical decision-making. First you must decide whether to use an SGA for your patient with a nonpsychotic disorder.
Second-generation antipsychotics (SGAs) show efficacy in so many psychotic and nonpsychotic disorders that a specific therapeutic action for each disorder is highly doubtful. One might ask, then: What do they improve, and how do they do it?
The complete answer is beyond current understanding, unfortunately. We do know, however, that SGAs have not shown efficacy for treating nonpsychotic disorders that first-generation antipsychotics (FGAs) did not show—except perhaps for maintenance treatment in bipolar disorder.
Calming action. The major clinical action of SGAs appears to be in calming patients, which also was the first therapeutic effect attributed to the FGA chlorpromazine. This calming effect would explain SGAs’ efficacy in treating agitation, aggressiveness, anxiety, and possibly mania. Other clinical effects specific to psychosis and possibly to depression are possible.
Receptor-blocking action. SGAs’ D2 and 5-HT2A receptor-blocking activity may explain much of the drugs’ therapeutic effect. However, if SGAs’ effect on nonpsychotic symptoms derives from their action on nondopaminergic receptors, then individual SGAs would vary widely in efficacy and pure dopaminergic agents such as amisulpride would be ineffective.
SGAs also bind at other receptor sites, and the clinical importance of this may vary from patient to patient, drug to drug, and dose to dose.4
Knowing, for example, that antipsychotics have been shown to increase mortality and cerebrovascular events in older patients might make you less likely to prescribe an SGA for a patient with dementia-related agitation. No other pharmacologic treatment has shown clear efficacy for these patients, however, so other factors are important to consider, including:
- patient history and clinical characteristics
- potential side effects
- individual therapeutic response to previous medications.
Table 2
SGA uses in nonpsychotic disorders supported by evidence
from published double-blind clinical trials*
| SGA | Unipolar depression | OCD | Anxiety disorders | Dementia | Developmental disorders | Borderline personality disorder |
|---|---|---|---|---|---|---|
| Aripiprazole | Yes | |||||
| Clozapine | ||||||
| Olanzapine | Yes | Yes | Yes | Yes | Yes | |
| Quetiapine | Yes | |||||
| Risperidone | Yes | Yes | Yes | Yes | ||
| Ziprasidone | ||||||
| * Not including studies of bipolar disorder | ||||||
| OCD: obsessive-compulsive disorder | ||||||
| SGA: second-generation antipsychotic | ||||||
Dementia
Most Alzheimer’s patients—75% to 90%—experience behavioral problems during this progressive dementia. Double-blind studies have found risperidone (mean dosage ~1 mg/d) and olanzapine (mean dosage 5 to 10 mg/d) effective in reducing agitation and aggression, even in nonpsychotic patients with Alzheimer’s disease or vascular dementia.5,6 Quetiapine, ≤100 mg/d, was not more effective than placebo in reducing agitation.7 One study comparing IM olanzapine with IM lorazepam and placebo in acute agitation found both active treatments more effective than placebo.8
CATIE-AD—sponsored by the National Institute of Mental Health—compared olanzapine, risperidone, and quetiapine with placebo in 421 outpatients with behavioral symptoms such as psychosis, agitation, or aggressiveness.1 No significant differences were seen in overall effectiveness (measured as discontinuation for any cause9), although patients receiving olanzapine (mean dosage 5.5 mg/d) or risperidone (mean dosage 1 mg/d) had lower discontinuation rates for lack of efficacy than those receiving placebo.
Unfortunately, the results of the first phase of CATIE-AD provide no clear guidance on the therapeutic strategy to use in dementia. Its findings do suggest two secondary conclusions, however, about using SGAs for patients with dementia:
- Because quetiapine, mean dosage 56.5 mg/d, was not more effective than placebo on any measures, consider higher dosages when using this agent.
- Close attention to preventing and treating SGAs’ side effects is the key to effectively treating agitation and psychosis in dementia.
Recommendation. Nonpharmacologic interventions are an important part of treating behavioral problems in patients with dementia.13,14 Antipsychotics—particularly SGAs—have shown efficacy for psychosis and agitation in these patients and remain the first therapeutic option. The CATIE-AD investigators recommend that clinicians evaluate potential risks and benefits of pharmacotherapy and discuss these with patients and caregivers.1 Also:
- Consider which SGAs have the lowest risk of causing side effects for an individual patient.
- Start with low dosages and increase as needed, based on efficacy and tolerability.
Bipolar disorder
Acute mania. Five SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute mania (Table 1). Large double-blind studies supporting this indication show that SGAs have efficacy in treating mania as monotherapy and in combination with lithium or divalproex.15 These clinical trials included patients who were not psychotic at baseline.
Antipsychotic dosages in these studies were within the ranges used in schizophrenia treatment studies. Combining an SGA with lithium or divalproex generally yields greater reductions in mania rating scale scores, higher response rates, and higher remission rates than using lithium or divalproex alone. No published study has compared SGAs with each other in mania, but differences in efficacy among these compounds are likely to be small.16
Bipolar depression. SGAs’ efficacy in bipolar depression has been evaluated in double-blind studies, and quetiapine and the olanzapine/fluoxetine combination are FDA-approved for this indication.
Olanzapine plus fluoxetine was more effective in improving depressive symptoms than olanzapine alone in a double-blind study of 833 adults with depressive symptoms of bipolar I disorder, as measured by Montgomery-Åsburg Depression Rating Scale (MADRS) scores. Olanzapine alone was more effective than placebo. Mean dosages were olanzapine, 7.4 mg/d, and fluoxetine, 39.3 mg/d, in combination therapy and olanzapine, 9.7 mg/d, as monotherapy.
MADRS scores indicated that combination therapy—but not olanzapine alone—improved core depressive symptoms such as sadness, lassitude, inability to feel, and pessimistic thoughts.17
Quetiapine. A double-blind, placebo-controlled trial (BOLDER I) evaluated quetiapine in 542 outpatients experiencing a major depressive episode associated with bipolar I or II disorder. After 8 weeks, quetiapine at 300 or 600 mg/d was more effective than placebo in reducing depressive symptoms, as measured by MADRS score changes.
Response rates were 58% with quetiapine and 36% with placebo; remission rates were 53% with quetiapine and 28% with placebo. Most symptoms, including core depression items, improved significantly with quetiapine, compared with placebo.18 Results of a second double-blind study (BOLDER II) have been presented at conferences but have not been fully published.
Risperidone. A smaller double-blind study compared risperidone plus placebo, paroxetine plus placebo, and risperidone plus paroxetine in 30 patients in the depressed phase of bipolar I or II disorder. Patients continued taking mood stabilizers during the study. After 12 weeks, depressive symptoms improved significantly in all three groups, with no significant differences.19
Maintenance therapy. Olanzapine and aripiprazole are FDA-approved for maintenance therapy in bipolar disorder (Table 1).
Unipolar depression
FGAs have shown efficacy in depression in multiple controlled studies.20 SGAs have been evaluated mostly as add-on therapies in antidepressant-resistant depression.
Olanzapine. Shelton et al21 compared olanzapine monotherapy, fluoxetine monotherapy, and combined treatment in 34 nonpsychotic, treatment-resistant depressed subjects. Olanzapine plus fluoxetine was more effective than either agent alone. A subsequent double-blind study, however, showed similar efficacy after 8 weeks among the three treatments and nortriptyline monotherapy. Patients in the double-blind trial appeared to respond more rapidly to combined treatment than to the monotherapies.22
Risperidone. A multiphase study of the efficacy of risperidone augmentation in treatment-resistant major depression began when 489 outpatients (2% with psychotic symptoms) received open-label citalopram, 20 to 60 mg/d. After 4 to 6 weeks, 386 nonresponders entered the augmentation phase with open-label risperidone, 0.25 to 2 mg/d. After 4 to 6 weeks of combination therapy, 241 (63%) patients whose symptoms resolved entered a double-blind discontinuation phase, in which they were randomly assigned to augmentation with risperidone or placebo, while on citalopram.
Median time to relapse during the double-blind phase was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates after 24 weeks were 53.3% and 54.6%, respectively.23 This study showed that the improvement observed after adding risperidone was not sustained over time.
Quetiapine. In a prospective single-blind study, paroxetine augmented with quetiapine, 200 mg/d, was compared to paroxetine alone in major depression with anxiety.24 Combination therapy was more effective in improving anxiety and depression symptoms.
Others. Open-label, add-on studies indicate that aripiprazole and ziprasidone can improve treatment-resistant depression.25-27
Anxiety disorders
OCD. SGAs also have been investigated as augmentation therapy for patients with OCD resistant to SRIs. A single-blind study of 27 patients found adjunctive quetiapine more effective than placebo in improving OCD symptoms.28 SGAs were more effective than placebo as augmentation therapy to SRIs for treatment-refractory OCD in double-blind, placebo-controlled studies using mean dosages of:
In other trials:
- A small double-blind study of patients with social anxiety disorder found olanzapine monotherapy more effective than placebo.34
- Low-dose risperidone (mean dosage 1.1 mg/d) improved core symptoms of generalized anxiety disorder in a 5-week, double-blind, placebo-controlled trial.35
- Some authors have reported clinical improvement of panic disorder with olanzapine augmentation.36
Developmental disorders
Antipsychotics represent one-third of all filled psychotropic prescriptions for individuals with pervasive developmental disorders (PDD).37 Haloperidol and thioridazine are the only two FDA-approved FGAs for severe behavioral problems in PDD (and for hyperactivity with conduct disorders). Recently, risperidone received FDA approval for the treatment of irritability associated with autistic disorder in children.
Risperidone—the most-studied SGA in the PDD population—has shown efficacy in autism and in PDD not otherwise specified. Risperidone at dosages >3 mg/d improved repetitive behavior and aggression in adult patients.38
In children with autism, risperidone can improve tantrums, aggression, and self-injury. In a study of risperidone’s effect on autism’s core symptoms, the authors reported improvements in repetitive and stereotyped behavior but not in social relatedness or verbal communication.39
Double-blind studies have shown positive effects on aggression and behavioral disturbances in children with conduct disorder, oppositional defiant disorder, and other disruptive disorders, developmentally delayed adolescents, and mentally retarded subjects of various ages.40-42 Children and adolescents appear to be more sensitive than adults to risperidone’s side effects such as weight gain, EPS, and pancreatitis.
Personality disorders
Antipsychotics have been recommended for paranoid ideas and psychotic-like symptoms in borderline personality disorder and in paranoid personality disorder.43
Olanzapine. A 24-week, double-blind study found low-dose olanzapine (mean dosage 5.3 mg/d) more effective than placebo for anxiety, interpersonal sensitivity, paranoia, and anger/hostility in women with borderline personality disorder.44
In another double-blind study, 12 weeks of olanzapine therapy (mean 6.9 mg/d) was more effective than placebo for inappropriate anger in borderline personality disorder, as measured by a modified Clinical Global Impression scale.45
Others. Anger and hostility improved more with aripiprazole, 15 mg/d, than with placebo in an 8-week double-blind study of patients with borderline personality disorder.46 Quetiapine, risperidone, ziprasidone, and clozapine have shown efficacy in open-label studies and case reports.
Related resources
- Boos J. Off label use–label off use? Ann Oncol 2003;14(1):1-5.
- Blum RS. Legal considerations in off-label medication prescribing. Arch Intern Med 2002;162(15):1777-9.
- Jeste DV, Dolder CR. Treatment of non-schizophrenic disorders: focus on atypical antipsychotics. J Psychiatr Res 2004;38(1):73-103.
- Food and Drug Administration. Searchable catalog of FDA-approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda.
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Citalopram • Celexa
- Clozapine • Clozaril
- Divalproex • Depakote
- Fluoxetine • Prozac
- Haloperidol • Haldol
- Nortriptyline • Pamelor, Aventyl
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Dr. Trémeau receives grant/research support from Eli Lilly and Company.
Dr. Citrome receives grant/research support from AstraZeneca, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Research Foundation, and Pfizer; is a consultant to Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Jazz Pharmaceuticals, and GlaxoSmithKline; and is a speaker for Abbott Laboratories, AstraZeneca, Eli Lilly and Company, and Pfizer.
1. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-38.
2. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-6.
3. Buckley PF. New antipsychotic agents: emerging clinical profiles. J Clin Psychiatry 1999;60(suppl 1):12-7.
4. Shayegan DK, Stahl SM. Atypical antipsychotics: matching receptor profile to individual patient’s clinical profile. CNS Spectr 2004;9(10 suppl 11):6-14.
5. Jeste DV, Dolder CR, Nayak GV, Salzman C. Atypical antipsychotics in elderly patients with dementia or schizophrenia: review of recent literature. Harv Rev Psychiatry 2005;13(6):340-51.
6. Carson S, McDonagh MS, Peterson K. A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia. J Am Geriatr Soc 2006;54(2):354-61.
7. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. BMJ 2005;330(7496):874.-
8. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):494-504.
9. Schneider LS, Tariot PN, Lyketsos CG, et al. National Institute of Mental Health Antipsychotic Trials of Intervention Effectiveness (CATIE). Alzheimer disease trial methodology. Am J Geriatr Psychiatry 2001;9:346-60.
10. Kennedy J, Deberdt W, Siegal A, et al. Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer’s dementia. Int J Geriatr Psychiatry 2005;20(11):1020-7.
11. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. April 11, 2005. Available at: http://www.fda.gov/Cder/drug/advisory/antipsychotics.htm. Accessed October 17, 2006.
12. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005;353(22):2335-41.
13. Rabins P, Bland W, Bright-Long L, et al. from the Work Group on Alzheimer’s disease and related dementias. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. American Psychiatric Association Practice Guideline 1997. Available at http://www.psych.org/psych_pract/ treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
14. Mittelman MS, Ferris SH, Shulman E, et al. A family intervention to delay nursing home placement of patients with Alzheimer’s disease: a random control trial. JAMA 1996;276:1725-31.
15. Citrome L, Goldberg JF, Stahl SM. Toward convergence in the medication treatment of bipolar disorder and schizophrenia. Harv Rev Psychiatry 2005;13(1):28-42.
16. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006;67(4):509-16.
17. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.
18. Calabrese JR, Keck PE, Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60.
19. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004;65(12):1715-9.
20. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord 1982;4(3):173-93.
21. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158(1):131-4.
22. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.
23. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006;31(11):2505-13.
24. Yargic LI, Corapcioglu A, Kocabasoglu N, et al. A prospective randomized single-blind, multicenter trial comparing the efficacy and safety of paroxetine with and without quetiapine therapy in depression associated with anxiety. Int J Psychiatry Clin Pract 2004;8:205-11.
25. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66(10):1326-30.
26. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004;65(2):217-21.
27. Simon JS, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005;66(10):1216-20.
28. Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002;17(3):115-9.
29. McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
30. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 2004;65(4):565-8.
31. Denys D, de Geus F, van Megen HJ, Westenberg HG. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004;65(8):1040-8.
32. Bartzokis G, Lu PH, Turner J, et al. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol Psychiatry 2005;57(5):474-9.
33. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry 2002;159(10):1777-9.
34. Barnett SD, Kramer ML, Casat CD, et al. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol 2002;16(4):365-8.
35. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2005;66(10):1321-5.
36. Khaldi S, Kornreich C, Dan B, Pelc I. Usefulness of olanzapine in refractory panic attacks. J Clin Psychopharmacol 2003;23(1):100-1.
37. Lott IT, McGregor M, Engelman L, et al. Longitudinal prescribing patterns for psychoactive medications in community-based individuals with developmental disabilities: utilization of pharmacy records. J Intellect Disabil Res 2004;48(Pt 6):563-71.
38. McDougle CJ, Holmes JP, Carlson DC, et al. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998;55(7):633-41.
39. McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162(6):1142-8.
40. Vanden Borre R, Vermote R, Buttiens M, et al. Risperidone as addon therapy in behavioural disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatr Scand 1993;87(3):167-71.
41. Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, Melman CT. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities. J Clin Psychiatry 2001;62(4):239-48.
42. Snyder R, Turgay A, Aman M, et al; Risperidone Conduct Study Group. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
43. Oldham JM, Gabbard GO, Goin MK, et al, from the workgroup on borderline personality disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association Practice Guideline 2001. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
44. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study. J Clin Psychiatry 2001;62(11):849-54.
45. Bogenschutz MP, George Nurnberg H. Olanzapine versus placebo in the treatment of borderline personality disorder. J Clin Psychiatry 2004;65(1):104-9.
46. Nickel MK, Muehlbacher M, Nickel C, et al. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2006;163(5):833-8.
Controlled clinical trial results can help you make two prescribing decisions:
- Is an antipsychotic the right choice for this patient?
- If yes, which agent?
Prescribing antipsychotics off-label can be worthwhile when a patient gets better, but even then two worries remain:
- Most uses of antipsychotics for nonpsychotic illness are not evidence-based.
- This practice may expose clinicians to liability if the patient gets worse.
Consider the use of second-generation antipsychotics (SGAs) to manage acute behaviors in patients with dementia. The FDA ordered a black box warning in 2005 that SGAs may increase mortality risk in older patients. In October, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) reported that SGAs’ side effects offset their benefits when compared with placebo (see Will CATIE-AD change dementia treatment?).1
What do you do when FDA-approved drugs fail to help your patient with dementia, unipolar depression, anxiety disorders, or other nonpsychotic symptoms, and SGAs may be the next consideration? The answers lie in managing side effects and knowing which antipsychotic uses are supported by data from controlled clinical trials, which we review here.
- FGAs showed efficacy for nonpsychotic disorders
- SGAs are associated with a lower risk of EPS and tardive dyskinesia at therapeutic dosages, compared with FGAs
- Many patients fail to respond adequately to medications approved for their illnesses
- Evidence on SGAs’ efficacy in nonpsychotic disorders has grown substantially in the past 10 years.
EPS: extrapyramidal symptoms
FGA: first-generation antipsychotic
SGA: second-generation antipsychotic
Prescribing considerations
For a variety of reasons (Box 1), SGAs have rapidly assumed a major role in treating nonpsychotic disorders. Thirty-one percent of psychotropics are dispensed off-label,2 and Buckley3 reported in a 3-state survey that 70% of SGA prescriptions were written for indications other than schizophrenia.
Using antipsychotics for nonpsychotic symptoms is a longstanding clinical practice. In schizophrenia patients, antipsychotics have been shown to improve psychotic and nonpsychotic symptoms: agitation, violence, negative symptoms, social isolation, depression, suicidality, anxiety, insomnia, poor appetite, compulsions, cognition, smoking, alcohol and drug use, polydipsia, tardive dyskinesia, and tardive dystonia. Some clinicians may view these reports as evidence that antipsychotics might relieve these symptoms in patients with nonpsychotic disorders as well, but the issue is more complicated than that (Box 2).4
Caveats. SGAs do offer clinicians unique tools; no other class of psychotropics can claim efficacy in psychotic disorders, bipolar disorder, depression, and other disorders we describe in this review. On the other hand:
- Although some SGAs are approved for bipolar disorder and one was recently approved to treat irritability in autism (Table 1), most SGA uses in nonpsychotic disorders are off-label and supported by few—if any—large, randomized, controlled trials.
- Antipsychotics can cause the very symptoms they relieve, including depression, obsessive-compulsive disorder (OCD), anxiety, poorer cognition, agitation, mania, insomnia, and abnormal movements.
- Few controlled studies have compared SGAs to usual first-line treatments; most have evaluated SGAs as adjuncts to other psychotropics—such as serotonin reuptake inhibitors (SRIs)—for patients with treatment-resistant disorders.
- Published head-to-head studies have rarely compared the efficacy of various SGAs in treating nonpsychotic disorders.
- Long-term safety studies of SGAs for nonpsychotic indications have not been done.
Table 1
Bipolar and other nonpsychotic indications FDA-approved for SGAs
| SGA | Bipolar mania | Bipolar depression | Bipolar maintenance | Other |
|---|---|---|---|---|
| Aripiprazole | Acute mania or mixed episodes | Bipolar I disorder, most recent episode manic or mixed | ||
| Clozapine | Risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders | |||
| Olanzapine | Acute mania or mixed episodes; monotherapy or with lithium or valproate for manic episodes | Bipolar disorder maintenance monotherapy | ||
| Olanzapine/fluoxetine combination | Bipolar depressive episodes | |||
| Quetiapine | Acute manic episodes; monotherapy or with lithium or valproate | Bipolar depressive episodes | ||
| Risperidone | Acute mania or mixed episodes; monotherapy or with lithium or valproate | Irritability in autism | ||
| Ziprasidone | Acute manic or mixed episodes | |||
| SGA: second-generation antipsychotic (oral forms) | ||||
Prescribing decisions. SGA’s potential adverse effects complicate clinical decision-making. First you must decide whether to use an SGA for your patient with a nonpsychotic disorder.
Second-generation antipsychotics (SGAs) show efficacy in so many psychotic and nonpsychotic disorders that a specific therapeutic action for each disorder is highly doubtful. One might ask, then: What do they improve, and how do they do it?
The complete answer is beyond current understanding, unfortunately. We do know, however, that SGAs have not shown efficacy for treating nonpsychotic disorders that first-generation antipsychotics (FGAs) did not show—except perhaps for maintenance treatment in bipolar disorder.
Calming action. The major clinical action of SGAs appears to be in calming patients, which also was the first therapeutic effect attributed to the FGA chlorpromazine. This calming effect would explain SGAs’ efficacy in treating agitation, aggressiveness, anxiety, and possibly mania. Other clinical effects specific to psychosis and possibly to depression are possible.
Receptor-blocking action. SGAs’ D2 and 5-HT2A receptor-blocking activity may explain much of the drugs’ therapeutic effect. However, if SGAs’ effect on nonpsychotic symptoms derives from their action on nondopaminergic receptors, then individual SGAs would vary widely in efficacy and pure dopaminergic agents such as amisulpride would be ineffective.
SGAs also bind at other receptor sites, and the clinical importance of this may vary from patient to patient, drug to drug, and dose to dose.4
Knowing, for example, that antipsychotics have been shown to increase mortality and cerebrovascular events in older patients might make you less likely to prescribe an SGA for a patient with dementia-related agitation. No other pharmacologic treatment has shown clear efficacy for these patients, however, so other factors are important to consider, including:
- patient history and clinical characteristics
- potential side effects
- individual therapeutic response to previous medications.
Table 2
SGA uses in nonpsychotic disorders supported by evidence
from published double-blind clinical trials*
| SGA | Unipolar depression | OCD | Anxiety disorders | Dementia | Developmental disorders | Borderline personality disorder |
|---|---|---|---|---|---|---|
| Aripiprazole | Yes | |||||
| Clozapine | ||||||
| Olanzapine | Yes | Yes | Yes | Yes | Yes | |
| Quetiapine | Yes | |||||
| Risperidone | Yes | Yes | Yes | Yes | ||
| Ziprasidone | ||||||
| * Not including studies of bipolar disorder | ||||||
| OCD: obsessive-compulsive disorder | ||||||
| SGA: second-generation antipsychotic | ||||||
Dementia
Most Alzheimer’s patients—75% to 90%—experience behavioral problems during this progressive dementia. Double-blind studies have found risperidone (mean dosage ~1 mg/d) and olanzapine (mean dosage 5 to 10 mg/d) effective in reducing agitation and aggression, even in nonpsychotic patients with Alzheimer’s disease or vascular dementia.5,6 Quetiapine, ≤100 mg/d, was not more effective than placebo in reducing agitation.7 One study comparing IM olanzapine with IM lorazepam and placebo in acute agitation found both active treatments more effective than placebo.8
CATIE-AD—sponsored by the National Institute of Mental Health—compared olanzapine, risperidone, and quetiapine with placebo in 421 outpatients with behavioral symptoms such as psychosis, agitation, or aggressiveness.1 No significant differences were seen in overall effectiveness (measured as discontinuation for any cause9), although patients receiving olanzapine (mean dosage 5.5 mg/d) or risperidone (mean dosage 1 mg/d) had lower discontinuation rates for lack of efficacy than those receiving placebo.
Unfortunately, the results of the first phase of CATIE-AD provide no clear guidance on the therapeutic strategy to use in dementia. Its findings do suggest two secondary conclusions, however, about using SGAs for patients with dementia:
- Because quetiapine, mean dosage 56.5 mg/d, was not more effective than placebo on any measures, consider higher dosages when using this agent.
- Close attention to preventing and treating SGAs’ side effects is the key to effectively treating agitation and psychosis in dementia.
Recommendation. Nonpharmacologic interventions are an important part of treating behavioral problems in patients with dementia.13,14 Antipsychotics—particularly SGAs—have shown efficacy for psychosis and agitation in these patients and remain the first therapeutic option. The CATIE-AD investigators recommend that clinicians evaluate potential risks and benefits of pharmacotherapy and discuss these with patients and caregivers.1 Also:
- Consider which SGAs have the lowest risk of causing side effects for an individual patient.
- Start with low dosages and increase as needed, based on efficacy and tolerability.
Bipolar disorder
Acute mania. Five SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute mania (Table 1). Large double-blind studies supporting this indication show that SGAs have efficacy in treating mania as monotherapy and in combination with lithium or divalproex.15 These clinical trials included patients who were not psychotic at baseline.
Antipsychotic dosages in these studies were within the ranges used in schizophrenia treatment studies. Combining an SGA with lithium or divalproex generally yields greater reductions in mania rating scale scores, higher response rates, and higher remission rates than using lithium or divalproex alone. No published study has compared SGAs with each other in mania, but differences in efficacy among these compounds are likely to be small.16
Bipolar depression. SGAs’ efficacy in bipolar depression has been evaluated in double-blind studies, and quetiapine and the olanzapine/fluoxetine combination are FDA-approved for this indication.
Olanzapine plus fluoxetine was more effective in improving depressive symptoms than olanzapine alone in a double-blind study of 833 adults with depressive symptoms of bipolar I disorder, as measured by Montgomery-Åsburg Depression Rating Scale (MADRS) scores. Olanzapine alone was more effective than placebo. Mean dosages were olanzapine, 7.4 mg/d, and fluoxetine, 39.3 mg/d, in combination therapy and olanzapine, 9.7 mg/d, as monotherapy.
MADRS scores indicated that combination therapy—but not olanzapine alone—improved core depressive symptoms such as sadness, lassitude, inability to feel, and pessimistic thoughts.17
Quetiapine. A double-blind, placebo-controlled trial (BOLDER I) evaluated quetiapine in 542 outpatients experiencing a major depressive episode associated with bipolar I or II disorder. After 8 weeks, quetiapine at 300 or 600 mg/d was more effective than placebo in reducing depressive symptoms, as measured by MADRS score changes.
Response rates were 58% with quetiapine and 36% with placebo; remission rates were 53% with quetiapine and 28% with placebo. Most symptoms, including core depression items, improved significantly with quetiapine, compared with placebo.18 Results of a second double-blind study (BOLDER II) have been presented at conferences but have not been fully published.
Risperidone. A smaller double-blind study compared risperidone plus placebo, paroxetine plus placebo, and risperidone plus paroxetine in 30 patients in the depressed phase of bipolar I or II disorder. Patients continued taking mood stabilizers during the study. After 12 weeks, depressive symptoms improved significantly in all three groups, with no significant differences.19
Maintenance therapy. Olanzapine and aripiprazole are FDA-approved for maintenance therapy in bipolar disorder (Table 1).
Unipolar depression
FGAs have shown efficacy in depression in multiple controlled studies.20 SGAs have been evaluated mostly as add-on therapies in antidepressant-resistant depression.
Olanzapine. Shelton et al21 compared olanzapine monotherapy, fluoxetine monotherapy, and combined treatment in 34 nonpsychotic, treatment-resistant depressed subjects. Olanzapine plus fluoxetine was more effective than either agent alone. A subsequent double-blind study, however, showed similar efficacy after 8 weeks among the three treatments and nortriptyline monotherapy. Patients in the double-blind trial appeared to respond more rapidly to combined treatment than to the monotherapies.22
Risperidone. A multiphase study of the efficacy of risperidone augmentation in treatment-resistant major depression began when 489 outpatients (2% with psychotic symptoms) received open-label citalopram, 20 to 60 mg/d. After 4 to 6 weeks, 386 nonresponders entered the augmentation phase with open-label risperidone, 0.25 to 2 mg/d. After 4 to 6 weeks of combination therapy, 241 (63%) patients whose symptoms resolved entered a double-blind discontinuation phase, in which they were randomly assigned to augmentation with risperidone or placebo, while on citalopram.
Median time to relapse during the double-blind phase was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates after 24 weeks were 53.3% and 54.6%, respectively.23 This study showed that the improvement observed after adding risperidone was not sustained over time.
Quetiapine. In a prospective single-blind study, paroxetine augmented with quetiapine, 200 mg/d, was compared to paroxetine alone in major depression with anxiety.24 Combination therapy was more effective in improving anxiety and depression symptoms.
Others. Open-label, add-on studies indicate that aripiprazole and ziprasidone can improve treatment-resistant depression.25-27
Anxiety disorders
OCD. SGAs also have been investigated as augmentation therapy for patients with OCD resistant to SRIs. A single-blind study of 27 patients found adjunctive quetiapine more effective than placebo in improving OCD symptoms.28 SGAs were more effective than placebo as augmentation therapy to SRIs for treatment-refractory OCD in double-blind, placebo-controlled studies using mean dosages of:
In other trials:
- A small double-blind study of patients with social anxiety disorder found olanzapine monotherapy more effective than placebo.34
- Low-dose risperidone (mean dosage 1.1 mg/d) improved core symptoms of generalized anxiety disorder in a 5-week, double-blind, placebo-controlled trial.35
- Some authors have reported clinical improvement of panic disorder with olanzapine augmentation.36
Developmental disorders
Antipsychotics represent one-third of all filled psychotropic prescriptions for individuals with pervasive developmental disorders (PDD).37 Haloperidol and thioridazine are the only two FDA-approved FGAs for severe behavioral problems in PDD (and for hyperactivity with conduct disorders). Recently, risperidone received FDA approval for the treatment of irritability associated with autistic disorder in children.
Risperidone—the most-studied SGA in the PDD population—has shown efficacy in autism and in PDD not otherwise specified. Risperidone at dosages >3 mg/d improved repetitive behavior and aggression in adult patients.38
In children with autism, risperidone can improve tantrums, aggression, and self-injury. In a study of risperidone’s effect on autism’s core symptoms, the authors reported improvements in repetitive and stereotyped behavior but not in social relatedness or verbal communication.39
Double-blind studies have shown positive effects on aggression and behavioral disturbances in children with conduct disorder, oppositional defiant disorder, and other disruptive disorders, developmentally delayed adolescents, and mentally retarded subjects of various ages.40-42 Children and adolescents appear to be more sensitive than adults to risperidone’s side effects such as weight gain, EPS, and pancreatitis.
Personality disorders
Antipsychotics have been recommended for paranoid ideas and psychotic-like symptoms in borderline personality disorder and in paranoid personality disorder.43
Olanzapine. A 24-week, double-blind study found low-dose olanzapine (mean dosage 5.3 mg/d) more effective than placebo for anxiety, interpersonal sensitivity, paranoia, and anger/hostility in women with borderline personality disorder.44
In another double-blind study, 12 weeks of olanzapine therapy (mean 6.9 mg/d) was more effective than placebo for inappropriate anger in borderline personality disorder, as measured by a modified Clinical Global Impression scale.45
Others. Anger and hostility improved more with aripiprazole, 15 mg/d, than with placebo in an 8-week double-blind study of patients with borderline personality disorder.46 Quetiapine, risperidone, ziprasidone, and clozapine have shown efficacy in open-label studies and case reports.
Related resources
- Boos J. Off label use–label off use? Ann Oncol 2003;14(1):1-5.
- Blum RS. Legal considerations in off-label medication prescribing. Arch Intern Med 2002;162(15):1777-9.
- Jeste DV, Dolder CR. Treatment of non-schizophrenic disorders: focus on atypical antipsychotics. J Psychiatr Res 2004;38(1):73-103.
- Food and Drug Administration. Searchable catalog of FDA-approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda.
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Citalopram • Celexa
- Clozapine • Clozaril
- Divalproex • Depakote
- Fluoxetine • Prozac
- Haloperidol • Haldol
- Nortriptyline • Pamelor, Aventyl
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Dr. Trémeau receives grant/research support from Eli Lilly and Company.
Dr. Citrome receives grant/research support from AstraZeneca, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Research Foundation, and Pfizer; is a consultant to Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Jazz Pharmaceuticals, and GlaxoSmithKline; and is a speaker for Abbott Laboratories, AstraZeneca, Eli Lilly and Company, and Pfizer.
Controlled clinical trial results can help you make two prescribing decisions:
- Is an antipsychotic the right choice for this patient?
- If yes, which agent?
Prescribing antipsychotics off-label can be worthwhile when a patient gets better, but even then two worries remain:
- Most uses of antipsychotics for nonpsychotic illness are not evidence-based.
- This practice may expose clinicians to liability if the patient gets worse.
Consider the use of second-generation antipsychotics (SGAs) to manage acute behaviors in patients with dementia. The FDA ordered a black box warning in 2005 that SGAs may increase mortality risk in older patients. In October, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) reported that SGAs’ side effects offset their benefits when compared with placebo (see Will CATIE-AD change dementia treatment?).1
What do you do when FDA-approved drugs fail to help your patient with dementia, unipolar depression, anxiety disorders, or other nonpsychotic symptoms, and SGAs may be the next consideration? The answers lie in managing side effects and knowing which antipsychotic uses are supported by data from controlled clinical trials, which we review here.
- FGAs showed efficacy for nonpsychotic disorders
- SGAs are associated with a lower risk of EPS and tardive dyskinesia at therapeutic dosages, compared with FGAs
- Many patients fail to respond adequately to medications approved for their illnesses
- Evidence on SGAs’ efficacy in nonpsychotic disorders has grown substantially in the past 10 years.
EPS: extrapyramidal symptoms
FGA: first-generation antipsychotic
SGA: second-generation antipsychotic
Prescribing considerations
For a variety of reasons (Box 1), SGAs have rapidly assumed a major role in treating nonpsychotic disorders. Thirty-one percent of psychotropics are dispensed off-label,2 and Buckley3 reported in a 3-state survey that 70% of SGA prescriptions were written for indications other than schizophrenia.
Using antipsychotics for nonpsychotic symptoms is a longstanding clinical practice. In schizophrenia patients, antipsychotics have been shown to improve psychotic and nonpsychotic symptoms: agitation, violence, negative symptoms, social isolation, depression, suicidality, anxiety, insomnia, poor appetite, compulsions, cognition, smoking, alcohol and drug use, polydipsia, tardive dyskinesia, and tardive dystonia. Some clinicians may view these reports as evidence that antipsychotics might relieve these symptoms in patients with nonpsychotic disorders as well, but the issue is more complicated than that (Box 2).4
Caveats. SGAs do offer clinicians unique tools; no other class of psychotropics can claim efficacy in psychotic disorders, bipolar disorder, depression, and other disorders we describe in this review. On the other hand:
- Although some SGAs are approved for bipolar disorder and one was recently approved to treat irritability in autism (Table 1), most SGA uses in nonpsychotic disorders are off-label and supported by few—if any—large, randomized, controlled trials.
- Antipsychotics can cause the very symptoms they relieve, including depression, obsessive-compulsive disorder (OCD), anxiety, poorer cognition, agitation, mania, insomnia, and abnormal movements.
- Few controlled studies have compared SGAs to usual first-line treatments; most have evaluated SGAs as adjuncts to other psychotropics—such as serotonin reuptake inhibitors (SRIs)—for patients with treatment-resistant disorders.
- Published head-to-head studies have rarely compared the efficacy of various SGAs in treating nonpsychotic disorders.
- Long-term safety studies of SGAs for nonpsychotic indications have not been done.
Table 1
Bipolar and other nonpsychotic indications FDA-approved for SGAs
| SGA | Bipolar mania | Bipolar depression | Bipolar maintenance | Other |
|---|---|---|---|---|
| Aripiprazole | Acute mania or mixed episodes | Bipolar I disorder, most recent episode manic or mixed | ||
| Clozapine | Risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders | |||
| Olanzapine | Acute mania or mixed episodes; monotherapy or with lithium or valproate for manic episodes | Bipolar disorder maintenance monotherapy | ||
| Olanzapine/fluoxetine combination | Bipolar depressive episodes | |||
| Quetiapine | Acute manic episodes; monotherapy or with lithium or valproate | Bipolar depressive episodes | ||
| Risperidone | Acute mania or mixed episodes; monotherapy or with lithium or valproate | Irritability in autism | ||
| Ziprasidone | Acute manic or mixed episodes | |||
| SGA: second-generation antipsychotic (oral forms) | ||||
Prescribing decisions. SGA’s potential adverse effects complicate clinical decision-making. First you must decide whether to use an SGA for your patient with a nonpsychotic disorder.
Second-generation antipsychotics (SGAs) show efficacy in so many psychotic and nonpsychotic disorders that a specific therapeutic action for each disorder is highly doubtful. One might ask, then: What do they improve, and how do they do it?
The complete answer is beyond current understanding, unfortunately. We do know, however, that SGAs have not shown efficacy for treating nonpsychotic disorders that first-generation antipsychotics (FGAs) did not show—except perhaps for maintenance treatment in bipolar disorder.
Calming action. The major clinical action of SGAs appears to be in calming patients, which also was the first therapeutic effect attributed to the FGA chlorpromazine. This calming effect would explain SGAs’ efficacy in treating agitation, aggressiveness, anxiety, and possibly mania. Other clinical effects specific to psychosis and possibly to depression are possible.
Receptor-blocking action. SGAs’ D2 and 5-HT2A receptor-blocking activity may explain much of the drugs’ therapeutic effect. However, if SGAs’ effect on nonpsychotic symptoms derives from their action on nondopaminergic receptors, then individual SGAs would vary widely in efficacy and pure dopaminergic agents such as amisulpride would be ineffective.
SGAs also bind at other receptor sites, and the clinical importance of this may vary from patient to patient, drug to drug, and dose to dose.4
Knowing, for example, that antipsychotics have been shown to increase mortality and cerebrovascular events in older patients might make you less likely to prescribe an SGA for a patient with dementia-related agitation. No other pharmacologic treatment has shown clear efficacy for these patients, however, so other factors are important to consider, including:
- patient history and clinical characteristics
- potential side effects
- individual therapeutic response to previous medications.
Table 2
SGA uses in nonpsychotic disorders supported by evidence
from published double-blind clinical trials*
| SGA | Unipolar depression | OCD | Anxiety disorders | Dementia | Developmental disorders | Borderline personality disorder |
|---|---|---|---|---|---|---|
| Aripiprazole | Yes | |||||
| Clozapine | ||||||
| Olanzapine | Yes | Yes | Yes | Yes | Yes | |
| Quetiapine | Yes | |||||
| Risperidone | Yes | Yes | Yes | Yes | ||
| Ziprasidone | ||||||
| * Not including studies of bipolar disorder | ||||||
| OCD: obsessive-compulsive disorder | ||||||
| SGA: second-generation antipsychotic | ||||||
Dementia
Most Alzheimer’s patients—75% to 90%—experience behavioral problems during this progressive dementia. Double-blind studies have found risperidone (mean dosage ~1 mg/d) and olanzapine (mean dosage 5 to 10 mg/d) effective in reducing agitation and aggression, even in nonpsychotic patients with Alzheimer’s disease or vascular dementia.5,6 Quetiapine, ≤100 mg/d, was not more effective than placebo in reducing agitation.7 One study comparing IM olanzapine with IM lorazepam and placebo in acute agitation found both active treatments more effective than placebo.8
CATIE-AD—sponsored by the National Institute of Mental Health—compared olanzapine, risperidone, and quetiapine with placebo in 421 outpatients with behavioral symptoms such as psychosis, agitation, or aggressiveness.1 No significant differences were seen in overall effectiveness (measured as discontinuation for any cause9), although patients receiving olanzapine (mean dosage 5.5 mg/d) or risperidone (mean dosage 1 mg/d) had lower discontinuation rates for lack of efficacy than those receiving placebo.
Unfortunately, the results of the first phase of CATIE-AD provide no clear guidance on the therapeutic strategy to use in dementia. Its findings do suggest two secondary conclusions, however, about using SGAs for patients with dementia:
- Because quetiapine, mean dosage 56.5 mg/d, was not more effective than placebo on any measures, consider higher dosages when using this agent.
- Close attention to preventing and treating SGAs’ side effects is the key to effectively treating agitation and psychosis in dementia.
Recommendation. Nonpharmacologic interventions are an important part of treating behavioral problems in patients with dementia.13,14 Antipsychotics—particularly SGAs—have shown efficacy for psychosis and agitation in these patients and remain the first therapeutic option. The CATIE-AD investigators recommend that clinicians evaluate potential risks and benefits of pharmacotherapy and discuss these with patients and caregivers.1 Also:
- Consider which SGAs have the lowest risk of causing side effects for an individual patient.
- Start with low dosages and increase as needed, based on efficacy and tolerability.
Bipolar disorder
Acute mania. Five SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute mania (Table 1). Large double-blind studies supporting this indication show that SGAs have efficacy in treating mania as monotherapy and in combination with lithium or divalproex.15 These clinical trials included patients who were not psychotic at baseline.
Antipsychotic dosages in these studies were within the ranges used in schizophrenia treatment studies. Combining an SGA with lithium or divalproex generally yields greater reductions in mania rating scale scores, higher response rates, and higher remission rates than using lithium or divalproex alone. No published study has compared SGAs with each other in mania, but differences in efficacy among these compounds are likely to be small.16
Bipolar depression. SGAs’ efficacy in bipolar depression has been evaluated in double-blind studies, and quetiapine and the olanzapine/fluoxetine combination are FDA-approved for this indication.
Olanzapine plus fluoxetine was more effective in improving depressive symptoms than olanzapine alone in a double-blind study of 833 adults with depressive symptoms of bipolar I disorder, as measured by Montgomery-Åsburg Depression Rating Scale (MADRS) scores. Olanzapine alone was more effective than placebo. Mean dosages were olanzapine, 7.4 mg/d, and fluoxetine, 39.3 mg/d, in combination therapy and olanzapine, 9.7 mg/d, as monotherapy.
MADRS scores indicated that combination therapy—but not olanzapine alone—improved core depressive symptoms such as sadness, lassitude, inability to feel, and pessimistic thoughts.17
Quetiapine. A double-blind, placebo-controlled trial (BOLDER I) evaluated quetiapine in 542 outpatients experiencing a major depressive episode associated with bipolar I or II disorder. After 8 weeks, quetiapine at 300 or 600 mg/d was more effective than placebo in reducing depressive symptoms, as measured by MADRS score changes.
Response rates were 58% with quetiapine and 36% with placebo; remission rates were 53% with quetiapine and 28% with placebo. Most symptoms, including core depression items, improved significantly with quetiapine, compared with placebo.18 Results of a second double-blind study (BOLDER II) have been presented at conferences but have not been fully published.
Risperidone. A smaller double-blind study compared risperidone plus placebo, paroxetine plus placebo, and risperidone plus paroxetine in 30 patients in the depressed phase of bipolar I or II disorder. Patients continued taking mood stabilizers during the study. After 12 weeks, depressive symptoms improved significantly in all three groups, with no significant differences.19
Maintenance therapy. Olanzapine and aripiprazole are FDA-approved for maintenance therapy in bipolar disorder (Table 1).
Unipolar depression
FGAs have shown efficacy in depression in multiple controlled studies.20 SGAs have been evaluated mostly as add-on therapies in antidepressant-resistant depression.
Olanzapine. Shelton et al21 compared olanzapine monotherapy, fluoxetine monotherapy, and combined treatment in 34 nonpsychotic, treatment-resistant depressed subjects. Olanzapine plus fluoxetine was more effective than either agent alone. A subsequent double-blind study, however, showed similar efficacy after 8 weeks among the three treatments and nortriptyline monotherapy. Patients in the double-blind trial appeared to respond more rapidly to combined treatment than to the monotherapies.22
Risperidone. A multiphase study of the efficacy of risperidone augmentation in treatment-resistant major depression began when 489 outpatients (2% with psychotic symptoms) received open-label citalopram, 20 to 60 mg/d. After 4 to 6 weeks, 386 nonresponders entered the augmentation phase with open-label risperidone, 0.25 to 2 mg/d. After 4 to 6 weeks of combination therapy, 241 (63%) patients whose symptoms resolved entered a double-blind discontinuation phase, in which they were randomly assigned to augmentation with risperidone or placebo, while on citalopram.
Median time to relapse during the double-blind phase was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates after 24 weeks were 53.3% and 54.6%, respectively.23 This study showed that the improvement observed after adding risperidone was not sustained over time.
Quetiapine. In a prospective single-blind study, paroxetine augmented with quetiapine, 200 mg/d, was compared to paroxetine alone in major depression with anxiety.24 Combination therapy was more effective in improving anxiety and depression symptoms.
Others. Open-label, add-on studies indicate that aripiprazole and ziprasidone can improve treatment-resistant depression.25-27
Anxiety disorders
OCD. SGAs also have been investigated as augmentation therapy for patients with OCD resistant to SRIs. A single-blind study of 27 patients found adjunctive quetiapine more effective than placebo in improving OCD symptoms.28 SGAs were more effective than placebo as augmentation therapy to SRIs for treatment-refractory OCD in double-blind, placebo-controlled studies using mean dosages of:
In other trials:
- A small double-blind study of patients with social anxiety disorder found olanzapine monotherapy more effective than placebo.34
- Low-dose risperidone (mean dosage 1.1 mg/d) improved core symptoms of generalized anxiety disorder in a 5-week, double-blind, placebo-controlled trial.35
- Some authors have reported clinical improvement of panic disorder with olanzapine augmentation.36
Developmental disorders
Antipsychotics represent one-third of all filled psychotropic prescriptions for individuals with pervasive developmental disorders (PDD).37 Haloperidol and thioridazine are the only two FDA-approved FGAs for severe behavioral problems in PDD (and for hyperactivity with conduct disorders). Recently, risperidone received FDA approval for the treatment of irritability associated with autistic disorder in children.
Risperidone—the most-studied SGA in the PDD population—has shown efficacy in autism and in PDD not otherwise specified. Risperidone at dosages >3 mg/d improved repetitive behavior and aggression in adult patients.38
In children with autism, risperidone can improve tantrums, aggression, and self-injury. In a study of risperidone’s effect on autism’s core symptoms, the authors reported improvements in repetitive and stereotyped behavior but not in social relatedness or verbal communication.39
Double-blind studies have shown positive effects on aggression and behavioral disturbances in children with conduct disorder, oppositional defiant disorder, and other disruptive disorders, developmentally delayed adolescents, and mentally retarded subjects of various ages.40-42 Children and adolescents appear to be more sensitive than adults to risperidone’s side effects such as weight gain, EPS, and pancreatitis.
Personality disorders
Antipsychotics have been recommended for paranoid ideas and psychotic-like symptoms in borderline personality disorder and in paranoid personality disorder.43
Olanzapine. A 24-week, double-blind study found low-dose olanzapine (mean dosage 5.3 mg/d) more effective than placebo for anxiety, interpersonal sensitivity, paranoia, and anger/hostility in women with borderline personality disorder.44
In another double-blind study, 12 weeks of olanzapine therapy (mean 6.9 mg/d) was more effective than placebo for inappropriate anger in borderline personality disorder, as measured by a modified Clinical Global Impression scale.45
Others. Anger and hostility improved more with aripiprazole, 15 mg/d, than with placebo in an 8-week double-blind study of patients with borderline personality disorder.46 Quetiapine, risperidone, ziprasidone, and clozapine have shown efficacy in open-label studies and case reports.
Related resources
- Boos J. Off label use–label off use? Ann Oncol 2003;14(1):1-5.
- Blum RS. Legal considerations in off-label medication prescribing. Arch Intern Med 2002;162(15):1777-9.
- Jeste DV, Dolder CR. Treatment of non-schizophrenic disorders: focus on atypical antipsychotics. J Psychiatr Res 2004;38(1):73-103.
- Food and Drug Administration. Searchable catalog of FDA-approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda.
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Citalopram • Celexa
- Clozapine • Clozaril
- Divalproex • Depakote
- Fluoxetine • Prozac
- Haloperidol • Haldol
- Nortriptyline • Pamelor, Aventyl
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Dr. Trémeau receives grant/research support from Eli Lilly and Company.
Dr. Citrome receives grant/research support from AstraZeneca, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Research Foundation, and Pfizer; is a consultant to Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Jazz Pharmaceuticals, and GlaxoSmithKline; and is a speaker for Abbott Laboratories, AstraZeneca, Eli Lilly and Company, and Pfizer.
1. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-38.
2. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-6.
3. Buckley PF. New antipsychotic agents: emerging clinical profiles. J Clin Psychiatry 1999;60(suppl 1):12-7.
4. Shayegan DK, Stahl SM. Atypical antipsychotics: matching receptor profile to individual patient’s clinical profile. CNS Spectr 2004;9(10 suppl 11):6-14.
5. Jeste DV, Dolder CR, Nayak GV, Salzman C. Atypical antipsychotics in elderly patients with dementia or schizophrenia: review of recent literature. Harv Rev Psychiatry 2005;13(6):340-51.
6. Carson S, McDonagh MS, Peterson K. A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia. J Am Geriatr Soc 2006;54(2):354-61.
7. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. BMJ 2005;330(7496):874.-
8. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):494-504.
9. Schneider LS, Tariot PN, Lyketsos CG, et al. National Institute of Mental Health Antipsychotic Trials of Intervention Effectiveness (CATIE). Alzheimer disease trial methodology. Am J Geriatr Psychiatry 2001;9:346-60.
10. Kennedy J, Deberdt W, Siegal A, et al. Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer’s dementia. Int J Geriatr Psychiatry 2005;20(11):1020-7.
11. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. April 11, 2005. Available at: http://www.fda.gov/Cder/drug/advisory/antipsychotics.htm. Accessed October 17, 2006.
12. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005;353(22):2335-41.
13. Rabins P, Bland W, Bright-Long L, et al. from the Work Group on Alzheimer’s disease and related dementias. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. American Psychiatric Association Practice Guideline 1997. Available at http://www.psych.org/psych_pract/ treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
14. Mittelman MS, Ferris SH, Shulman E, et al. A family intervention to delay nursing home placement of patients with Alzheimer’s disease: a random control trial. JAMA 1996;276:1725-31.
15. Citrome L, Goldberg JF, Stahl SM. Toward convergence in the medication treatment of bipolar disorder and schizophrenia. Harv Rev Psychiatry 2005;13(1):28-42.
16. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006;67(4):509-16.
17. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.
18. Calabrese JR, Keck PE, Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60.
19. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004;65(12):1715-9.
20. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord 1982;4(3):173-93.
21. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158(1):131-4.
22. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.
23. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006;31(11):2505-13.
24. Yargic LI, Corapcioglu A, Kocabasoglu N, et al. A prospective randomized single-blind, multicenter trial comparing the efficacy and safety of paroxetine with and without quetiapine therapy in depression associated with anxiety. Int J Psychiatry Clin Pract 2004;8:205-11.
25. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66(10):1326-30.
26. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004;65(2):217-21.
27. Simon JS, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005;66(10):1216-20.
28. Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002;17(3):115-9.
29. McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
30. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 2004;65(4):565-8.
31. Denys D, de Geus F, van Megen HJ, Westenberg HG. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004;65(8):1040-8.
32. Bartzokis G, Lu PH, Turner J, et al. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol Psychiatry 2005;57(5):474-9.
33. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry 2002;159(10):1777-9.
34. Barnett SD, Kramer ML, Casat CD, et al. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol 2002;16(4):365-8.
35. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2005;66(10):1321-5.
36. Khaldi S, Kornreich C, Dan B, Pelc I. Usefulness of olanzapine in refractory panic attacks. J Clin Psychopharmacol 2003;23(1):100-1.
37. Lott IT, McGregor M, Engelman L, et al. Longitudinal prescribing patterns for psychoactive medications in community-based individuals with developmental disabilities: utilization of pharmacy records. J Intellect Disabil Res 2004;48(Pt 6):563-71.
38. McDougle CJ, Holmes JP, Carlson DC, et al. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998;55(7):633-41.
39. McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162(6):1142-8.
40. Vanden Borre R, Vermote R, Buttiens M, et al. Risperidone as addon therapy in behavioural disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatr Scand 1993;87(3):167-71.
41. Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, Melman CT. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities. J Clin Psychiatry 2001;62(4):239-48.
42. Snyder R, Turgay A, Aman M, et al; Risperidone Conduct Study Group. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
43. Oldham JM, Gabbard GO, Goin MK, et al, from the workgroup on borderline personality disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association Practice Guideline 2001. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
44. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study. J Clin Psychiatry 2001;62(11):849-54.
45. Bogenschutz MP, George Nurnberg H. Olanzapine versus placebo in the treatment of borderline personality disorder. J Clin Psychiatry 2004;65(1):104-9.
46. Nickel MK, Muehlbacher M, Nickel C, et al. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2006;163(5):833-8.
1. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-38.
2. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-6.
3. Buckley PF. New antipsychotic agents: emerging clinical profiles. J Clin Psychiatry 1999;60(suppl 1):12-7.
4. Shayegan DK, Stahl SM. Atypical antipsychotics: matching receptor profile to individual patient’s clinical profile. CNS Spectr 2004;9(10 suppl 11):6-14.
5. Jeste DV, Dolder CR, Nayak GV, Salzman C. Atypical antipsychotics in elderly patients with dementia or schizophrenia: review of recent literature. Harv Rev Psychiatry 2005;13(6):340-51.
6. Carson S, McDonagh MS, Peterson K. A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia. J Am Geriatr Soc 2006;54(2):354-61.
7. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. BMJ 2005;330(7496):874.-
8. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):494-504.
9. Schneider LS, Tariot PN, Lyketsos CG, et al. National Institute of Mental Health Antipsychotic Trials of Intervention Effectiveness (CATIE). Alzheimer disease trial methodology. Am J Geriatr Psychiatry 2001;9:346-60.
10. Kennedy J, Deberdt W, Siegal A, et al. Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer’s dementia. Int J Geriatr Psychiatry 2005;20(11):1020-7.
11. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. April 11, 2005. Available at: http://www.fda.gov/Cder/drug/advisory/antipsychotics.htm. Accessed October 17, 2006.
12. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005;353(22):2335-41.
13. Rabins P, Bland W, Bright-Long L, et al. from the Work Group on Alzheimer’s disease and related dementias. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. American Psychiatric Association Practice Guideline 1997. Available at http://www.psych.org/psych_pract/ treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
14. Mittelman MS, Ferris SH, Shulman E, et al. A family intervention to delay nursing home placement of patients with Alzheimer’s disease: a random control trial. JAMA 1996;276:1725-31.
15. Citrome L, Goldberg JF, Stahl SM. Toward convergence in the medication treatment of bipolar disorder and schizophrenia. Harv Rev Psychiatry 2005;13(1):28-42.
16. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006;67(4):509-16.
17. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.
18. Calabrese JR, Keck PE, Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60.
19. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004;65(12):1715-9.
20. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord 1982;4(3):173-93.
21. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158(1):131-4.
22. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.
23. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006;31(11):2505-13.
24. Yargic LI, Corapcioglu A, Kocabasoglu N, et al. A prospective randomized single-blind, multicenter trial comparing the efficacy and safety of paroxetine with and without quetiapine therapy in depression associated with anxiety. Int J Psychiatry Clin Pract 2004;8:205-11.
25. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66(10):1326-30.
26. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004;65(2):217-21.
27. Simon JS, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005;66(10):1216-20.
28. Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002;17(3):115-9.
29. McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
30. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 2004;65(4):565-8.
31. Denys D, de Geus F, van Megen HJ, Westenberg HG. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004;65(8):1040-8.
32. Bartzokis G, Lu PH, Turner J, et al. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol Psychiatry 2005;57(5):474-9.
33. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry 2002;159(10):1777-9.
34. Barnett SD, Kramer ML, Casat CD, et al. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol 2002;16(4):365-8.
35. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2005;66(10):1321-5.
36. Khaldi S, Kornreich C, Dan B, Pelc I. Usefulness of olanzapine in refractory panic attacks. J Clin Psychopharmacol 2003;23(1):100-1.
37. Lott IT, McGregor M, Engelman L, et al. Longitudinal prescribing patterns for psychoactive medications in community-based individuals with developmental disabilities: utilization of pharmacy records. J Intellect Disabil Res 2004;48(Pt 6):563-71.
38. McDougle CJ, Holmes JP, Carlson DC, et al. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998;55(7):633-41.
39. McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162(6):1142-8.
40. Vanden Borre R, Vermote R, Buttiens M, et al. Risperidone as addon therapy in behavioural disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatr Scand 1993;87(3):167-71.
41. Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, Melman CT. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities. J Clin Psychiatry 2001;62(4):239-48.
42. Snyder R, Turgay A, Aman M, et al; Risperidone Conduct Study Group. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41(9):1026-36.
43. Oldham JM, Gabbard GO, Goin MK, et al, from the workgroup on borderline personality disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association Practice Guideline 2001. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed November 15, 2006.
44. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study. J Clin Psychiatry 2001;62(11):849-54.
45. Bogenschutz MP, George Nurnberg H. Olanzapine versus placebo in the treatment of borderline personality disorder. J Clin Psychiatry 2004;65(1):104-9.
46. Nickel MK, Muehlbacher M, Nickel C, et al. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2006;163(5):833-8.