Evidence-Based Reviews

Antipsychotics for patients without psychosis?

Current Psychiatry. 2006 December;5(12):33-44

References

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19. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004;65(12):1715-9.

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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.

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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.

If you decide to use an SGA, you then must choose among the available agents. Because head-to-head comparisons are lacking, consider data that exist for your patients’ nonpsychotic indications (Table 1 and Table 2).

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.

Other studies. In addition to common side effects observed with SGAs, controlled data suggest that olanzapine and quetiapine can worsen cognition in older patients with dementia.^7,10 SGAs—as well as FGAs—also have been associated with increased risk of cerebrovascular events (stroke and transient ischemic attacks) and mortality in this population.^11,12

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.