Leslie L. Citrome, MD, MPH

Here to discuss evidence-based practices in 

 is Leslie Citrome, MD, MPH, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York.

Dr Citrome is a scheduled speaker at this year's US Psychiatric and Mental Health Congress in Orlando, Florida. His presentation is titled “Agitation and Aggression: Managing the Acute Episode and Beyond, An Evidence-Based Approach.”

Articles

A video summarizing key points of a presentation titled “Agitation and Aggression: Managing the Acute Episode and Beyond, An Evidence-Based Approach.”

Evidence-Based Practices in Managing Agitation and Aggression

How can you apply the framework and philosophy of evidence-based medicine to the use of antipsychotic medication?Here to discuss is Leslie Citrome, MD, MPH. Dr Citrome is Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla. He is a scheduled speaker at this year's US Psychiatric and Mental Health Congress in Las Vegas.Here is a brief summary of some of the points Dr Citrome makes in his 5-minute audio presentation:
•Evidence-based medicine is not cookbook medicine. It means pairing your clinical judgment with the relevant scientific evidence and including your patients’ values and preferences into making a decision for your patient. It’s about individualizing therapy.
•Treatment effectiveness is not just efficacy; it is also the combination of efficacy plus tolerability plus adherence.
•When appraising evidence of a drug’s efficacy, number need to treat (NNT) and number needed to harm (NNH) are favorite tools. We can use these tools to indirectly compare the new antipsychotics with one another, for example. With ilopederidone, asenapine, and lurasidone, we can calculate where the data are available: how many patients does it require to be treated with any of these agents versus placebo before we can expect to encounter one additional responder? Those agents with a lower NNT would be expected to be more efficacious. We need to balance this as well with safety and tolerability outcomes. The product labels for each of these new agents list commonly encountered adverse effects. We can calculate NNH to cause (for example) sedation or akathesia or weight gain of at least 7% from baseline. By doing so, we can figure out where these drugs indirectly compare with each other. For NNH, the higher the number the better. The NNH should be double digit so that we don’t encounter that harm very often.
•Other factors to consider when looking at the new agents include how often per day these agents are taken; does the drug need to be taken with or without a meal or liquids; what are the warnings regarding prolactin, QT prolongation, and perhaps pregnancy category . . . all these factors may be influential depending on the patient you are treating.Further reading:Citrome LL. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. September 2013. http://link.springer.com/article/10.1007/s40263-013-0105-7.Citrome LL. New second-generation long-acting injectable antipsychotics for the treatment of schizophrenia. Expert Rev Neurother. 2013;13:767-83.

Slideshows

How can you apply the framework and philosophy of evidence-based medicine to the use of antipsychotic medication? Here to discuss is Leslie L. Citrome, MD, MPH.

Evidence-Based Use of Antipsychotics: A Quick “How To”

Most patients with mental illness are not violent, and when violent behavior does occur, it is usually transient.

 Nevertheless, violent behavior is a challenging problem. Swanson and colleagues 

 provided evidence that demonstrated that schizophrenia and major mood disorders confer an elevated risk of violent behavior, and that risk is augmented by comorbid substance use disorders and by comorbid personality disorders.

Comorbid substance use disorders play a particularly important role in the development of violent behavior in schizophrenia. This was studied in a meta-analysis of violent criminality using data from 18,423 individuals with schizophrenia and other psychoses.

 The odds ratio for violent crime was 2.1 (95% confidence interval [CI], 1.7 - 2.7) without comorbidity, but it increased to 8.9 (95% CI, 5.4 - 14.7) with comorbidity. The difference between odds ratios indicated a marked effect of substance abuse on violent crime.

The clinical importance of this effect is underlined by the fact that risk for substance use disorders in schizophrenia is very high; lifetime prevalence of this comorbidity in schizophrenia is estimated at 47%.

 For these reasons, evaluation of comorbid substance use disorders is an important component of the clinical assessment of patients with schizophrenia. Management of comorbid substance use disorders must be an inherent part of the treatment plan.

Violent behavior is heterogeneous in origin, and its development is not limited to the context of mental illness.

 Therefore, management approaches that rely exclusively on psychopharmacology are frequently unsuccessful-not only because of incorrect societal context, but also because violent behavior in mental illness frequently results from nonadherence to treatment.

Acute management of agitation and violent behavior

Agitation is a common reason for presentation to an emergency department (ED); it can tip the decision for in-patient care and can be an obsta-cle to hospital discharge. Agitation can easily escalate to aggression and violent behavior, and thus acute agitation is considered a behavioral emergency that requires immediate action. In addition to nonpharmacological interventions related to managing crisis situations, medication approaches are vital.

Although oral medications can be effective, rapidity of onset of action is enhanced with the use of short-acting parenteral formulations that allow for maximal plasma levels to be reached more quickly. Lorazepam can be useful when the cause of the disturbed behavior is unclear and perhaps due to withdrawal from alcohol. It is reliably absorbed intramuscularly, has no active metabolites, and has a half-life of 10 to 20 hours; the usual dosage is 0.5 to 2 mg every 1 to 6 hours.

Caution is required with lorazepam when respiratory depression is a possibility. In addition, lorazepam should not be used for long-term daily use because of the problems that are associated with benzodiazepine use-tolerance, dependence, and withdrawal.

What is already known about treating aggression?


? Schizophrenia and major mood disorders confer an elevated risk of violent behavior, which is further raised by comorbid substance use disorders and by comorbid personality disorders. Intramuscular short-acting formulations of lorazepam, haloperidol, aripiprazole, olanzapine, and ziprasidone are available for the management of acute agitation and aggression. All available antipsychotics as well as mood stabilizers and other drugs have been used for the long-term management of violent behavior in mental illness. Clozapine has demonstrated superiority over other treatments.

What new information does this article provide?


? We update information on efficacy and safety of medications used for acute agitation and aggression, particularly intramuscular formulations.

What are the implications for psychiatric practice?


? Clozapine is the first-choice treatment for persistently violent patients with schizophrenia. It is not likely to be fully effective before an adequate dose (approximately 400 mg/d) is reached-often several weeks. Clozapine should not be prematurely discontinued during this escalation period. If necessary, another medication may be temporarily added to control violent behavior. If clozapine cannot be used, olanzapine may be a second choice. Other antipsychotics do not show any systematic differences in their antiaggressive effects.

The combination of intramuscular haloperidol with intramuscular lorazepam is also commonly used and is supported by a double-blind randomized clinical trial that compared intramuscular haloperidol 5 mg, intramuscular lorazepam 2 mg, or a combination of both in psychotic, agitated, and aggressive patients treated in EDs.

 However, continued use of haloperidol as a foundational antipsychotic would be suboptimal in schizophrenia or bipolar disorder. Consequently, there has been increased interest in intramuscular formulations of second-generation antipsychotics, of which 3 are available in the US: ziprasidone, olanzapine, and aripiprazole.

Intramuscular ziprasidone’s efficacy in reducing agitation was evidenced in 2 pivotal clinical trials that enrolled patients with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, or another psychotic disorder.

 Although the product label recommends a dose of 10 or 20 mg, the best dose appears to be 20 mg; this conclusion is based on the proportion of patients with a clinically relevant reduction in agitation-rating–scale scores.

A naturalistic study of intramuscular ziprasidone in patients who can have more severe levels of agitation than those participating in a randomized controlled study also supports the use of intramuscular ziprasidone as an effective treatment.

 Product labeling cautions prescribers regarding ziprasidone’s potential to prolong the QT interval and that the cyclodextrin excipient used in the formulation is cleared by renal filtration, which may be an issue in patients who have impaired renal function.

Intramuscular olanzapine was found to be effective in reducing agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.

 The recommended dose of olanzapine is 10 mg, but lower doses of 2.5 to 5 mg can be considered for medically vulnerable patients.

 Naturalistic studies of intramuscular olanzapine are also supportive of its effectiveness.

 The product label is cautionary regarding hypotension, bradycardia with or without hypotension, tachycardia, and syncope as reported during the clinical trials. Simultaneous injection of olanzapine and benzodiazepines is not recommended, and this advice is reinforced in a report of a case series in which comorbid medical conditions were noted to increase risk.

Study findings indicate that intramuscular aripiprazole reduces agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.

 The product label cautions clinicians regarding greater sedation and orthostatic hypotension with the combination of lorazepam and aripiprazole compared with aripiprazole alone.

Once past the acute phase, patients who are receiving intramuscular ziprasidone, olanzapine, or aripiprazole can be successfully transitioned to the oral counterpart of the medication.

Most of the evidence on long-term treatment of aggression in mental illness has been collected in patients with schizophrenia. There are very few controlled trials that were a priori designed to test antiaggressive treatments. Most of the data available were obtained in the form of clinical observations, uncontrolled chart reviews, and post hoc retrospective analyses of databases collected primarily for purposes other than the study of aggression. Antipsychotics are the mainstay of the long-term pharmacological treatment of aggression in schizophrenia.

Randomized controlled trials of antipsychotics are summarized in the 

. Two randomized, controlled, double-blind trials were designed a priori to study aggression in schizophrenia. The first trial compared clozapine, olanzapine, risperidone, and haloperidol in 157 patients with schizophrenia or schizoaffective disorder.

 The hostility item of the PANSS (Positive and Negative Syndrome Scale) was used as a proxy measure for aggression in the analyses. Clozapine was superior to risperidone and haloperidol (but not to olanzapine) in reducing hostility.

 Neither risperidone nor olanzapine showed superiority to haloperidol.

In the same randomized controlled trial, incidents of overt physical aggression were also recorded and analyzed.

 The results showed clozapine (and, in some analyses, all 3 atypicals) to be superior to haloperidol in antiaggressive efficacy, particularly after the first 24 days in the trial, when scheduled dose escalation of clozapine was completed. Thus, an important clinical take-home lesson from this study is that full effectiveness of clozapine cannot be expected until the patient has been exposed to an adequate-dose regimen. If aggressive behavior is a problem during the escalation period of clozapine, other medications need to be temporarily coadministered. Discontinuation of clozapine for lack of effectiveness during this period would be premature.

The second randomized double-blind trial compared clozapine, olanzapine, and risperidone in 110 patients with schizophrenia or schizo-affective disorder who were selected for being violent.

 For reducing overt physical aggression, clozapine was more efficacious than olanzapine, which was, in turn, more efficacious than haloperidol.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) has yielded important information about antiaggressive effects of antipsychotics.

 In the double-blind phase 1 trial, 1445 patients with chronic schizophrenia were randomly assigned to receive 1 of 5 antipsychotics: risperidone, olanzapine, quetiapine, ziprasidone, or perphenazine. They were then followed up for 6 months for violent behavior.

 Violence declined with all medications. The only difference between medications was that perphenazine showed greater violence reduction than quetiapine in some analyses.

Data acquired in the context of the European First Episode Schizophrenia Trial (EUFEST) were used to compare in post hoc analyses the effects of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility (assessed as a PANSS item).

 The results showed that at months 1 and 3, olanzapine was significantly superior to haloperidol, quetiapine, and amisulpride in reducing hostility.

, have shown the superiority of risperidone, quetiapine, and aripiprazole in comparison with placebo in terms of antiaggressive efficacy.

 The effects of ziprasidone could not be distinguished from those of other antipsychotics.

Thus, randomized controlled trials as well as uncontrolled studies strongly support the superiority of clozapine over other antipsychotics in reducing violent behavior. Emerging evidence suggests that olanzapine may be a good second choice if clozapine cannot be used. However, metabolic adverse effects of these medications must be taken into account when making individual clinical decisions.

Mood stabilizers (anticonvulsants and lithium)

Although not approved by the FDA for impulsive aggression, valproate is frequently prescribed as an adjunctive medication for patients with schizophrenia, perhaps with the expectation that impulse control will be improved.

 Satisfactory efficacy of adjunctive valproate in schizophrenia has been reported, and post hoc analysis of the hostility item of the PANSS has demonstrated valproate efficacy during the first week of treatment.

 However, these results could not be replicated; thus, the empirical data available do not support the efficacy of valproate as adjunctive treatment for violent patients with schizophrenia.

Lamotrigine has been tested as adjunctive treatment in schizophrenia, with contradictory results.

 Findings from a recent meta-analysis suggest that lamotrigine may be useful in the most severely ill patients who are clozapine-resistant.

A recent meta-analysis examined the effects of valproate, carbamazepine, and phenytoin in the treatment of aggression with associated impulsivity in various psychiatric disorders. The researchers found that the evidence is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity.

Another meta-analysis excluded patients with psychosis, organic brain disorder, and mental retardation and, thus, focused mainly on personality disorders.

 The effects of valproate, carbamazepine, phenytoin, levetiracetam, and lithium on aggression were analyzed. Some evidence of antiaggressive efficacy was found for carbamazepine, phenytoin, and lithium.

Lithium has been found to reduce aggressive behavior in mood disorders, particularly in bipolar disorder.

 There is some evidence of antiaggressive effects of mood stabilizers in personality disorders.

Although mood stabilizer treatment of aggression in schizophrenia is not supported by adequate empirical evidence and is not approved by the FDA, it is possible that it may be effective in some patients. Such use must be weighed against potential adverse effects. The effectiveness of adjunctive treatment must be closely monitored, and the treatment must be promptly discontinued if it fails to show clear benefits.

SSRIs were reported to reduce aggressive behavior in patients with personality disorders and in the intellectually disabled.

 Adjunctive citalopram showed antiaggressive efficacy in persistently violent schizophrenia inpatients in a study that awaits replication.

Several studies have been undertaken to test the efficacy of drugs in the management of aggression and hostility in patients with schizophrenia and other mood disorders. Clozapine was found to be most efficacious in reducing violent behavior in agitated patients with schizophrenia. However, clozapine is not likely to be fully effective against aggression before an optimal dose (approximately 400 mg/d) is reached, and dose titration may take several weeks. During the initial escalation period, clozapine should not be prematurely discontinued for apparent lack of effectiveness; if necessary, other medications can be added to clozapine temporarily to reduce aggressive behavior. If clozapine is contraindicated, olanzapine may be the second choice. Other antipsychotics do not show any systematic differences in their antiaggressive effects.

. 2 ed. Washington, DC: American Psychiatric Publishing, Inc; 2002.


 Swanson JW, Holzer CE 3rd, Ganju VK, Jono RT. Violence and psychiatric disorder in the community: evidence from the Epidemiologic Catchment Area surveys [published correction appears in 

 Fazel S, Gulati G, Linsell L, et al. Schizophrenia and violence: systematic review and meta-analysis. 

 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. 

 Volavka J, Swanson JW, Citrome LL. Understanding and managing violence in schizophrenia. In: Lieberman JA, Murray RM, eds. 

Comprehensive Care of Schizophrenia: A Textbook of Clinical Management

. 2nd ed. New York: Oxford University Press; 2012.


 Swartz MS, Swanson JW, Hiday VA, et al. Violence and severe mental illness: the effects of substance abuse and nonadherence to medication. 

 Greenblatt DJ, Shader RI, Franke K, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. 

 Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. 

 Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. 

 Lesem MD, Zajecka JM, Swift RH, et al. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients [published correction appears in 

 Daniel DG, Potkin SG, Reeves KR, et al. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. 

 Preval H, Klotz SG, Southard R, Francis A. Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. 

 Geodon (ziprasidone HCl) product information. 

http://www.pfizer.com/products/rx/rx_product_geodon.jsp

 Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. 

Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. 

 Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. 

 Zyprexa (olanzapine) product information. 

 San L, Arranz B, Querejeta I, et al. A naturalistic multicenter study of intramuscular olanzapine in the treatment of acutely agitated manic or schizophrenic patients. 

 Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. 

 Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. 

 Tran-Johnson TK, Sack DA, Marcus RN, et al. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. 

 Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. 

 Abilify (aripiprazole) product information. 

 Daniel DG, Zimbroff DL, Swift RH, Harrigan EP. The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy. 

Several studies have been undertaken to test the efficacy of drugs in the management of aggression and hostility in patients with schizophrenia and other mood disorders.

Psychopharmacology of Aggression and Violence in Mental Illness

You must keep your own records of this activity. Copy this information and include it in your continuing education file for reporting purposes.



CME LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CME LLC designates this educational activity for a maximum of 1.5 

. Physicians should only claim credit commensurate with the extent of their participation in the activity.

CME LLC is approved by the California Board of Registered Nursing, Provider No. CEP12748, and designates this educational activity for 1.5 contact hours for nurses.

The American Nurses Credentialing Center (ANCC) accepts 

toward recertification requirements.

The American Academy of Physician Assistants (AAPA) accepts 

 from organizations accredited by the ACCME.
 


Original release date 1/10. Approved for CME credit through January 2011.

After reading this article, you will be familiar with:

• The different arms of the CATIE study
• The use of number needed to treat and number needed to harm in appraising the clinical relevance of study results
• CATIE efficacy, tolerability, and safety results for the atypical antipsychotics as well as the representative typical antipsychotic, perphenazine
• The advantages/disadvantages of one antipsychotic over another



Who will benefit from reading this article?


Psychiatrists, child and adolescent psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

Efficacy variations among the atypical and typical antipsychotics result in overlaps between the 2 groups.

 Adverse-effect profiles differ as well. In general, typical antipsychotics have a greater propensity to cause extrapyramidal side effects, tardive dyskinesia, and prolactin elevations than do atypical anti-psychotics. The adverse effects associated with some atypical antipsychotics are more weight gain and greater disturbances in lipid and glucose regulation than are associated with typical antipsychotics. However, there is considerable heterogeneity among the individual agents in both classes and overlapping adverse effects.

 the philosophy of evidence-based medicine requires the thoughtful clinician to incorporate the best available research findings into an individualized treatment plan, and to take into account clinical experience and patient preferences. When selecting antipsychotics for patients with schizophrenia, the prescribing physician can approach this decision-making process using these principles of evidence-based medicine.

On the basis of the results from the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), this article reviews the principles of antipsychotic therapy selection based on individual patient profiles as it pertains to perphenazine (the representative typical anti-psychotic in the CATIE study), olanzapine, risperidone, quetiapine, ziprasidone, and clozapine. Using a basic tool of evidence-based medicine-effect size as measured by number needed to treat-demonstrates that we are better off having choices.

Simone is a 45-year-old African American woman whose schizophrenia was diagnosed when she was 22 years old. She has had about 5 brief hospitalizations for exacerbations of her symptoms, usually precipitated by nonadherence when her medications were changed to something she did not agree with. She lives in a basement apartment owned by her family and attends a day treatment program 3 times a week. Simone smokes about 10 cigarettes a day when she is able to afford them. She does not use street drugs or alcohol. Simone has a fraternal twin, Sabella, who also has schizophrenia.

Simone responds reasonably well to quetiapine or risperidone, but not to haloperidol, and she objects to extrapyramidal side effects, particularly akathisia. Simone’s mother and all of her maternal aunts have type 2 diabetes mellitus. Her body mass index is 29 kg/m

, and she eats high-fat foods and does not exercise. She is willing to take either quetiapine or risperidone and her clinician prescribes generic risperidone.

Simone presents with a number of conflicting issues, and the best medication option for Simone at this juncture is difficult to immediately ascertain. Fortunately, there are clinical trials that can help inform the clinician in making thoughtful individualized treatment decisions about antipsychotic medication switches. Simone is representative of ambulatory patients with schizophrenia who have been ill for a decade or more. Thus, she resembles the patients enrolled in the CATIE schizophrenia studies.

Approximately 1500 patients participated in at least one part of CATIE, and the study remains the largest randomized pragmatic clinical trial to date that compares the overall relative effectiveness of several of the atypical antipsychotics with each other as well as with a representative typical antipsychotic (perphenazine). Time to all-cause discontinuation was the primary outcome measure and represents the “real-world” usefulness of a medication. The assumption is that a patient will continue to use a medication (and a clinician will continue to prescribe it) if the medication is considered by all parties to be effective, safe, and tolerable.

One of the basic tools of evidence-based medicine used to appraise clinical trial data is number needed to treat.

 Number needed to treat answers the question: for how many patients do I need to prescribe medication X instead of medication Y before I would expect to encounter one additional success? If the number needed to treat for success of medication X versus medication Y is 5, then it would take 5 patients to be treated with X instead of Y before one additional patient has a successful outcome. The higher the number needed to treat, the less of a difference there is between medications X and Y. The lower the number needed to treat, the more compelling the difference is. 

(See Sidebar for how to calculate number needed to treat.)

CATIE outcomes can be reinterpreted using number needed to treat.

 Depending on the phase of CATIE, different antipsychotics had different rankings for overall effectiveness.

 The usefulness of CATIE in informing medical decision making is that the study consisted of several phases during which patients could discontinue their initial randomized medication and be re-randomized to another. Thus CATIE actually mimics clinical practice: if one antipsychotic does not work for any reason, another antipsychotic is tried. (See 

 for a summary of patient characteristics.)

Phase 1 demonstrated that all-cause discontinuation was lowest with olanzapine; risperidone and perphenazine also had advantages in terms of number needed to treat. Switching away from risperidone or olanzapine may also have an impact on all-cause discontinuation. This was observed in a post hoc analysis of patients randomly assigned to olanzapine or risperidone who also continued to take their baseline medication. These patients had significantly longer times until discontinuation than those who switched antipsychotics.

 Thus, switching antipsychotics is not necessarily a benign process.

An important caveat is that we do not know what exactly motivated the patients to participate in CATIE, nor do we know with any precision how effective or tolerable their medication regimens were before randomization.

What are the relative rankings of the different antipsychotics in phase 1? We can calculate the number needed to treat for pair-wise comparisons on all-cause discontinuation. The 95% confidence interval (CI) is provided for all comparisons that were statistically significant at the 

The lower the number needed to treat value, the bigger the advantage is for the antipsychotic relative to its comparator. For example, for every 6 patients randomized to olanzapine instead of quetiapine in phase 1, one additional patient will have completed the entire 18 months on the initially randomized medication (ie, successful in avoiding all-cause discontinuation). Likewise, for every 13 patients randomized to risperidone instead of quetiapine in phase 1, one additional patient will have avoided all-cause discontinuation. For this latter comparison, the 95% CI is considered “wide,” with 95% certainty, the actual difference between risperidone and quetiapine on all-cause discontinuation is somewhere between a low of every 7 patients to a high of every 54 patients.

CATIE also answers the question about what agent to switch to after a patient has had an unsuccessful trial with perphenazine. Phase 1B was an interim phase for those patients who had been randomized to perphenazine in phase 1 but who discontinued for any reason. Inadequate therapeutic effect was the reason why 48% of the participants in phase 1B discontinued perphenazine, and 32% discontinued it because of unacceptable adverse effects. Thus, the enrollees in phase 1B represent patients who did not do well enough because of either efficacy or tolerability issues on an older agent with relatively “tight” dopamine D2 receptor binding (perphenazine). In this phase, quetiapine (and olanzapine) performed relatively well, whereas risperidone, a “tighter” D2 blocking agent than olanzapine or quetiapine, did not (

). This difference between risperidone and quetiapine is the opposite of what was observed in phase 1 and, as will be discussed later, in phase 2T. Phase 1B demonstrates that number needed to treat values for all-cause discontinuation are highly dependent on which phase of CATIE is being scrutinized.

In view of the relative rankings of the different antipsychotics in CATIE phase 1, generic risperidone was not an unreasonable choice, especially given Simone’s past history of response. Moreover, should adherence become an issue, the availability of a depot formulation of risperidone is a definite plus. Unfortunately, 2 months after being placed on treatment with 4 mg of risperidone per day, Simone complained of feeling restless. Her clinician was of the opinion that the patient’s restlessness was due to akathisia. Simone was no longer willing to take risperidone. She did not want to wait to see if a reduction in dosage would decrease her subjective restlessness, nor did she want to take pro-pranolol to see if that would relieve her symptoms. Given Simone’s strong family history for type 2 diabetes mellitus and Simone’s elevated weight, as well as her unhealthy lifestyle, her clinician decided to treat her with ziprasidone. CATIE supports this decision as well.

The so-called ziprasidone pathway for phase 2, known as phase 2T, was designed to test whether ziprasidone had advantages over the other atypical antipsychotics for patients who discontinued phase 1 early because of poor tolerability. In reality, phase 2T is challenging to interpret because approximately equal numbers of patients who discontinued phase 1 because of poor efficacy entered phase 2T as those who discontinued phase 1 because of poor tolerability. The number needed to treat and the 95% CI for all-cause discontinuation are summarized in 

For all-cause discontinuation in phase 2T, the only 2 statistically significant results for number needed to treat were the comparisons of olanzapine or risperidone versus quetiapine. For every 6 patients randomized to olanzapine, or every 5 patients randomized to risperidone, instead of quetiapine, there was 1 additional patient taking olanzapine or risperidone who did not discontinue therapy prematurely. Ziprasidone did not demonstrate superiority on the global outcome of all-cause discontinuation. However, phase 2T did confirm the benign metabolic profile for ziprasidone and there were fewer discontinuations because of weight or metabolic concerns (

Of particular interest are the patients who gained more than 7% of their initial body weight. Of the 61 patients who did so in CATIE phase 1, 42% of those randomized to ziprasidone in phase 2T lost over 7% of their body weight, compared with 20% for risperidone, 7% for quetiapine, and 0% for olanzapine. This translates to number needed to treat comparing ziprasidone with risperidone (5), quetiapine (3), and olanzapine (3). For every 3 patients who gained more than 7% of their baseline weight in phase 1 and who were subsequently randomized to ziprasidone in phase 2 instead of olanzapine or quetiapine, an additional case of weight loss greater than 7% was observed.

Simone was given ziprasidone with some concerns on her part because she had never taken it before and was unsure whether it would work for her. She was also concerned about the need to change her schedule to take ziprasidone with a meal.

 However, she was interested to see if her weight would be better controlled.

Ongoing monitoring of weight continues to be necessary and amenability to a weight reduction program needs to be assessed. Monitoring weight at each patient visit allows the clinician to catch a problem early, before substantial weight gain has set in. It also underscores to both the patient and the clinician the importance of physical fitness. Weight management strategies include both psychoeducational and medication interventions; the latter technique is less successful than the former.

Simone is not particularly worried about rehospitalization-her symptoms were successfully managed throughout the crisis by increasing her attendance at her day treatment program from 3 times a week to every day. Her sister, Sabella, however, has had a stormier course, with rehospitalizations occurring almost every 6 months. Both Simone and Sabella are worried about their weight. Can we quantify trade-offs between avoidance of hospitalization versus weight gain?

The CATIE study informs us about balancing the risk of weight gain versus the risk of hospitalization caused by exacerbation of schizophrenia. In phase 1, the numbers needed to treat to avoid hospitalization for exacerbation of schizophrenia based on 1-year risk ratios (hospitalizations per total person-years of exposure) are listed in 

Although olanzapine had advantages regarding avoidance of hospitalization, it was associated with higher rates of weight gain in excess of 7% of baseline. Pairwise comparisons can be made and number needed to harm for weight gain can be calculated. Number needed to harm is an analogue of number needed to treat and is used when referring to undesirable outcomes. It is calculated the same way as number needed to treat. 

 provides the number needed to harm for weight gain.

For every pair-wise comparison, with the exception of olanzapine versus risperidone, avoidance of a hospitalization event would be encountered more frequently than weight gain in excess of 7% of baseline (number needed to treat is lower, ie, stronger, than number needed to harm). Ratios of number needed to harm to number needed to treat have been used to describe the likelihood of being helped or harmed.

 However, some patients may gain substantially more than 7% of their baseline weight. Weight gain and robust efficacy in the same patient poses a clinical dilemma.

Moreover, even though number needed to treat and number needed to harm can help predict how often events can occur, there are no guarantees of weight gain or loss, or of a drug’s effectiveness. The patient’s history remains the best predictor of treatment success or failure.

After unsuccessful trials of several antipsychotics, both Simone and Sabella are fed up. They want to try clozapine. What does CATIE tell us about switching from a first-line atypical antipsychotic to clozapine?

The “clozapine pathway” of phase 2 of CATIE, known as phase 2E, was designed to test what advantages there might be for switching to clozapine for patients who discontinued their phase 1 or phase 1B atypical antipsychotic because of poor efficacy. Fewer patients randomized to olanzapine in phase 1 entered phase 2E than 2T (19% vs 26%), but more patients who were randomized to quetiapine in phase 1 entered phase 2E than 2T (37% vs 31%). A possible confounder is that patients who entered phase 2E knew they could be randomized to clozapine, and once randomized knew if they were actually getting open-label clozapine versus double-blinded olanzapine, quetiapine, or risperidone. Hence, if they really wanted clozapine and did not get randomized to it, they may have been inclined to discontinue their anti-psychotic. The number needed to treat and the 95% CI for all-cause discontinuation are summarized in 

Statistically significant differences are evident for the comparisons of clozapine with risperidone or quetiapine; the number needed to treat showed an advantage for clozapine every 4 or 3 patients, respectively, in terms of all-cause discontinuation. The number needed to treat for clozapine versus olanzapine was 7, which indicates a respectable effect size difference that could have been statistically significant if only the sample size had been larger.

Simone and Sabella have heard that clozapine may be associated with hypersalivation. They ask how frequent a problem this is.

The importance of context when looking at treatment advantage

Sialorrhea is a common side effect of clozapine. Inspection of the clozapine product label reveals a reported frequency of 31% for hypersalivation.

 CATIE provides enough information to calculate the number needed to harm for sialorrhea, comparing clozapine with quetiapine, olanzapine, and risperidone, as outlined in 

For every 3 patients randomized to clozapine versus quetiapine, one additional case of sialorrhea was encountered. This is a strong effect size and emphasizes how common this adverse effect is with clozapine. However, if good efficacy is achieved, patients who take clozapine will tol-erate hypersalivation and will not stop their medication.

Individual patients have their own preferences and values regarding efficacy and tolerability goals. These may differ from what the clinician has in mind. Thus, although the practitioner may want to prioritize the diminution of hallucinations and delusions, the patient may desire mainly to feel less anxious and less dysphoric. Similarly, different patients may find different adverse effects of medications distressing-some may abhor tremors but others may not mind them.

Pragmatic clinical trials (such as CATIE) provide generalizable data that can be incorporated into medical decision making. In the different phases of CATIE, advantages were evident for each of the atypical antipsychotics and for the representative typical antipsychotic perphenazine, but all in different contexts.

Olanzapine had advantages in terms of all-cause discontinuation and efficacy, particularly in phase 1. It appears that the efficacy advantage of olanzapine drove its overall lower all-cause discontinuation rate. The disadvantage of olanzapine was discontinuation because of weight gain or metabolic effects; although this disadvantage was statistically significant, it did not reach the same level of magnitude as the number needed to treat advantage for efficacy.

Risperidone and perphenazine had advantages over quetiapine in phase 1 in terms of number needed to treat for all-cause discontinuation. Quetiapine (and olanzapine) had advantages in terms of all-cause discontinuation in phase 1B where perphenazine had failed. Clozapine was superior to risperidone and quetiapine for patients who discontinued an antipsychotic in phase 1 (or 1B) because of poor efficacy. Risperidone had advantages in terms of overall tolerability in phases 1, 2E, and 2T. Ziprasidone had the most benign metabolic profile, and in phase 2T it was associated with a higher likelihood of weight loss for patients who gained more than 7% of their initial body weight in phase 1.

CATIE can be viewed as a switch study. Switches offer both opportunity and risk. Data from CATIE demonstrate differences in overall effectiveness, but these differences depend on the individual patient context. Questions to ask include:

• Did therapy with a “tight” D2 binding agent fail?

• Did therapy fail because of lack of efficacy or tolerability?

• Is weight gain greater than 7% the predominant concern?

• Is the risk of hospitalization the predominant concern?

It will be necessary to match the expectations and requirements of the individual patient to a specific medication-one size does NOT fit all. Treating clinicians need access to all these medications to optimize treatment for each patient.

 Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. 

 Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and what it isn’t. 

 Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. 

 Stroup TS, Lieberman JA, McEvoy JP, et al; CATIE Investigators. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. 

 McEvoy JP, Lieberman JA, Stroup TS, et al; CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. 

 Stroup TS, Lieberman JA, McEvoy JP, et al; CATIE Investigators. Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. 

 Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. 

 Citrome L, Stroup TS. Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians? 

 Citrome L. Interpreting and applying the CATIE results: with CATIE, context is key, when sorting out phases 1, 1A, 1B, 2E, and 2T. 

http://www.psychiatrymmc.com/interpreting-and-applying-the-catie-results

 Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. 

 Citrome L. Using oral ziprasidone effectively: the food effect and dose-response. 

 Citrome L, Vreeland B. Schizophrenia, obesity, and antipsychotic medications: what can we do? 

 Karagianis J, Rosenbluth M, Tohen M, et al.

Reviewing CATIE for clinicians: balancing benefit and risk using evidence-based medicine tools. 

 Citrome L, Kantrowitz J. Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks. 

 Novartis. Clozaril (clozapine) tablets. Prescribing information. Revised July 2009. 

http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf

 Swartz MS, Wagner HR, Swanson JW, et al. Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study. 

 Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. 

CATIE can be viewed as a switch study. Switches offer both opportunity and risk. Data from CATIE demonstrate differences in overall effectiveness, but these differences depend on the individual patient context.

What to Make of CATIE: Are We Better Off With Atypical Antipsychotics?

The development of new atypical antipsychotics and their introduction to the U.S. market has been proceeding at a fast pace. The Table provides an overview of their indications, formulations available, dosing, efficacy and safety in typical adult patients. More detailed information on dosing, as well as on treatment-resistant schizophrenia, can be found elsewhere (Citrome et al., 2002; Citrome and Volavka, 2002). The most recent additions to the antipsychotic armamentarium, ziprasidone (Geodon) and aripiprazole (Abilify), differ from the previously available products in their mechanisms of action and side-effect profiles. Antipsychotic efficacy of these two agents appears similar to older agents, but definitive head-to-head, randomized clinical trials will be required to answer questions about relative efficacy. Also reviewed is information about a new intramuscular (IM) formulation of olanzapine (Zyprexa) and an indication for clozapine (Clozaril) recently approved by the U.S. Food and Drug Administration.

 agonist. This combination of activities, somewhat different from those of other antipsychotics, may be responsible for ziprasidone's pattern of side effects. Unlike most other antipsychotics, it does not have significant effects on weight, lipid profile or glucose metabolism. Furthermore, it shows low rate of persistent prolactin elevation and low incidence of extrapyramidal symptoms (EPS). Ziprasidone increases the QT

, however, and this particular side effect has raised concerns about its cardiac safety. Such prolongation increases the risk of torsade de pointes, a ventricular tachycardia-fibrillation with a characteristic electrocardiogram (ECG) presentation. Episodes of torsade de pointes may be brief and self-limiting. They may also be manifested by syncope. Torsade de pointes rarely progresses to typical ventricular fibrillation and death. This risk must be evaluated in the context of the fact that no cases of mortality from ziprasidone overdoses or torsade de pointes and no excess in sudden and unexpected deaths have so far been reported, even though by mid-2002 more than 150,000 patients received long-term treatment (Glassman and Bigger, 2002), and an overdose of 4020 mg of ziprasidone elicited only minor ECG changes (House, 2002).

Nevertheless, ziprasidone should not be co-administered with other agents--mostly antifungal and antibacterial drugs listed in the 

--that are known to prolong the QT interval. Furthermore, it should not be prescribed for patients with an overt cardiovascular disease or a history of cardiac arrhythmias. Electrocardiogram monitoring at baseline and then at regular intervals during ziprasidone treatment has been recommended by a group of experts (Marder et al., 2002), but the value of such monitoring has not been demonstrated. Perhaps the baseline ECG should be limited to patients over 55 years of age (Glassman and Bigger, 2002). Congenital prolongation of the QT interval is one of the circumstances that raise the risk of torsade de pointes; this condition may not be apparent without a baseline ECG. Actual cardiac risk of ziprasidone treatment remains to be assessed by long-term surveillance of a large number of treated cases, but the evidence available so far does not suggest that this is going to be a major problem. The risk of cardiac arrhythmia with ziprasidone (which may turn out to be small) must be weighed against the more established risks that have been associated with some other atypical antipsychotics (agranulocytosis, weight gain, glucose and lipid metabolism, and prolactin elevation, among others).

The antipsychotic efficacy of ziprasidone is presumably mediated by the combination of D

 antagonism. In double-blind studies of oral medication lasting four to six weeks, ziprasidone (80 mg/day to 160 mg/day) was generally superior to placebo in the treatment of schizophrenia or schizoaffective disorder (Daniel et al., 1999; Keck et al., 1998). Data from a four-week trial indicated that ziprasidone 160 mg/day has similar efficacy to haloperidol (Haldol) 15 mg/day (Goff et al., 1998). The availability of a short-acting IM formulation for acute psychosis with agitation is a major advantage of ziprasidone (Citrome, 2002). After an IM dose of 10 mg, peak plasma concentrations are reached within 30 minutes to 45 minutes, with concurrent clinically significant calming effect (FDA Psychopharmacological Drugs Advisory Committee, 2001b). Ziprasidone IM reduced agitated behavior more rapidly and with fewer EPS than IM haloperidol. Starting treatment of an acute schizophrenic episode with IM injections of an atypical antipsychotic like ziprasidone offers the possibility of a seamless transition to oral treatment with the same drug, obviating the necessity of switching from IM haloperidol to a generally more preferable atypical antipsychotic.

A short-acting IM formulation of olanzapine is expected to be launched in the United States in 2003 (Citrome, 2002). Peak plasma concentration after an IM injection is reached within 15 minutes to 30 minutes. In treating acute agitation in schizophrenia, 10 mg olanzapine IM was more effective than 7.5 mg haloperidol IM (and than IM placebo) at 15 minutes after the initial injection, and this advantage was sustained during the first hour after the injection (Wright et al., 2001). Similar results were reported in agitated patients with mania and with dementia (FDA Psychopharmacological Drugs Advisory Committee, 2001a).

 antagonist when dopaminergic activity (which may be causing psychotic symptoms) is increased, and as an agonist when the activity is decreased. Thus, instead of simply blocking the D

 receptor like other antipsychotics, it acts like a dopamine system stabilizer. This novel mechanism of action, different from other antipsychotics, may account for its different side-effect profile: it causes essentially no EPS, no elevation of prolactin levels and no clinically meaningful prolongation of the QT interval. At the same time, the antipsychotic efficacy of aripiprazole (15 mg/day to 30 mg/day) was similar to that of risperidone (Risperdal) (6 mg/day) or haloperidol (10 mg/day) in short-term clinical trials (Lieberman et al., 2002).

Increasing variations in mechanisms of action of atypical antipsychotics, side-effect profiles, and efficacy among the atypicals enable clinicians to tailor treatments to individual response, side-effect history, and current medical conditions.

Author | Leslie L. Citrome, MD, MPH

Articles

New content coming soon, please check back later.