Jan Volavka, MD, PhD

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

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 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. 

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 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. 

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Articles

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

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).

In a four-week, double-blind, randomized trial comparing two fixed-dose levels of aripiprazole (15 mg/day and 30 mg/day) with haloperidol (10 mg/day) and placebo in 414 patients with a primary diagnosis of schizophrenia or schizoaffective disorder, haloperidol and both doses of aripiprazole were found to be superior to placebo, and both medications appeared to have similar antipsychotic efficacy (Kane et al., 2002). Unlike haloperidol, however, neither dose of aripiprazole was associated with EPS or prolactin elevation. In the groups receiving haloperidol and 15 mg/day of aripiprazole, the percentage of patients showing a clinically significant weight gain (>7%) was significantly elevated (in comparison with placebo). Preliminary evidence suggests that weight gain is minimal over a 52-week period.

In December 2002, the FDA approved a new indication for clozapine: to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated in the International Suicide Prevention Trial (InterSePT), a two-year trial of 980 patients that compared clozapine to olanzapine. Clozapine treatment to reduce the risk of recurrent suicidal behavior should be continued for at least two years (Meltzer et al., 2003).

There is increasing evidence that clozapine also reduces the risk of recurrent aggressive behavior (Citrome et al., 2001; Volavka, 2002). It may also reduce alcohol and drug abuse problems among patients with schizophrenia (Drake et al., 2000), although the evidence for this is not based on controlled studies.

All atypical antipsychotics have a lower propensity for EPS, and some of them perhaps have better efficacy for negative, cognitive and mood symptoms, compared to typical antipsychotics. What differentiates these products? Ease of use is an important consideration, with clozapine carrying a significant burden for white blood cell count monitoring. Having to titrate dose over time rather than starting at an efficacious dose is also an obstacle, and here clozapine, quetiapine (Seroquel), ziprasidone and risperidone are at a disadvantage compared to aripiprazole and olanzapine. Once-a-day dosing is also preferable, particularly to enhance compliance, and here the product labeling favors risperidone, olanzapine and aripiprazole over ziprasidone, quetiapine and clozapine. Having a short-acting IM formulation available for emergency use gives ziprasidone and soon olanzapine an important advantage in the management of patients in situations where oral administration is difficult. The availability of liquid or dissolvable preparations such as with risperidone and olanzapine can be an alternative to intramuscular injection for selected patients. New depot preparations (risperidone depot is expected to become available in the United States in 2003) will differentiate these products from the others for patients who have difficulty with adhering to their medication regimen over the long-term.

The side-effect profiles of the atypical antipsychotics also differ. Although all have less risk for EPS than the conventional agents, among the atypical antipsychotics, risperidone and ziprasidone can lead to EPS at higher doses that are still within the product labeling. Weight gain can be seen for clozapine, olanzapine, and, to a lesser extent, risperidone or quetiapine, but ziprasidone is considered essentially weight-neutral. Sustained elevations in serum prolactin can be seen with patients on risperidone but usually not with the other atypical antipsychotics. As with EPS, however, prolactin elevation may be seen at higher doses of the other atypical antipsychotics, as illustrated by a recent case report of a 17-year-old female on ziprasidone 180 mg/day (Jordan, 2003).

 prolongation is a concern for ziprasidone but not for the others.

Less certain are any differences in efficacy. This issue is complicated by the very nature of the disease, where treatment response may be quite different at the beginning of the illness compared with 20 years after onset. The availability of head-to-head, randomized, double-blind clinical trials studying different treatment domains will be illustrative.

To date, there is one published randomized, double-blind study comparing effects of clozapine, risperidone, olanzapine and haloperidol on psychotic symptoms (Volavka et al., 2002) and on cognition (Bilder et al., 2002). The latter study showed superiority of olanzapine and risperidone (but not of clozapine) over haloperidol in improving global cognitive functioning. Presentations at national meetings have suggested that quetiapine (Mueller et al., 2002), ziprasidone (Loebel et al., 2002) and aripiprazole (Cornblatt et al., 2002) may also benefit cognition.

Efficacy in reducing negative symptoms has been noted for all atypical antipsychotics, with some evidence published (Kane et al., 2002) or presented at meetings (Kujawa et al., 2002; Loebel et al., 2002). For treatment-resistant patients, clozapine appears to be relatively effective against negative symptoms (Volavka et al., 2002).

Optimal dosing is still being actively investigated, with very little information regarding dose response available for quetiapine, ziprasidone and aripiprazole, other than initial recommendations from the manufacturer based on premarketing registration studies.

Recent developments in antipsychotics show no major breakthroughs in terms of antipsychotic efficacy, but they do promise treatments that are safer, easier to administer and more acceptable to patients. Increasing variation among the available medications should enable a knowledgeable clinician to tailor psychopharmacological treatments to suit the individual patient's personal preference, response and side-effect history, and current medical condition. Novel mechanisms of action of some recent antipsychotics such as aripiprazole are heuristically interesting and may lead to better understanding of the pathophysiology underlying schizophrenia.

 Bilder RM, Goldman RS, Volavka J et al. (2002), Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159(6):1018-1028 [see comment].


 Citrome L (2002), Atypical antipsychotics for acute agitation. New intramuscular options offer advantages. Postgrad Med 112(6):85-88, 94-96.


 Citrome L, Bilder RM, Volavka J (2002), Managing treatment-resistant schizophrenia: evidence from randomized clinical trials. Journal of Psychiatric Practice 8(4):205-215.


 Citrome L, Volavka J (2002), Optimal dosing of atypical antipsychotics in adults: a review of the current evidence. Harv Rev Psychiatry 10(5):280-291.


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www.fda.gov/ohrms/dockets/ac/01/briefing/3685b1_01_lilly.pdf

 FDA Psychopharmacological Drugs Advisory Committee (2001b), Briefing document for Ziprsidone Mesylate for Intramuscular Injection. 15 February 2001. Available at:

www.fda.gov/ohrms/dockets/ac/01/briefing/3685b2_01_pfizer.pdf

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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.

Jan Volavka, MD, PhD

Articles

Psychopharmacology of Aggression and Violence in Mental Illness

Recent Developments in Antipsychotic Use in Adults