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DOI: 10.1055/s-2002-31523
Psychopharmacological Treatment of Aggression
in Schizophrenic Patients
- Introduction
- Antipsychotics
- Benzodiazepines
- Mood stabilizers
- SSRIs
- Beta-blockers
- Other agents
- Conclusions
- References
Aggressive behavior is frequently observed in schizophrenic patients. More than 50 % of all psychiatric patients and 10 % of schizophrenic patients show aggressive symptoms varying from threatening behavior and agitation to assault. The pharmacological treatment of acute, persisting and repetitive aggression is a serious problem for other patients and staff members. Not only is violent behavior from mentally ill patients the most detrimental factor in their stigmatization, aggression is also a considerable direct source of danger for the patients themselves.
Based on rather limited evidence, a wide variety of medications for the pharmacological treatment of aggression has been recommended: typical and atypical antipsychotics, benzodiazepines, mood stabilizers, beta-blockers and selective serotonin reuptake inhibitors (SSRIs).
Most clinical information on treating aggression has been collected for atypical neuroleptics, particularly for clozapine. Several retrospective and open studies indicate its efficacy. Treatment duration of 6 months is recommended to induce a stable reduction of physical and verbal aggression. Severe side effects have very rarely been seen. At the moment, clozapine seems to be the first choice in aggression treatment. Within the last few years, about 10 articles were published showing that this is the most effective antiaggressive agent in the treatment of aggression and agitation in psychiatric patients, independent of psychiatric diagnosis. However, clozapine, like all the other substances used, does not have an established indication for the treatment of aggressive symptoms. Noncompliance with medication makes it difficult to choose the right preparation for the medication: tablets, liquids, intramuscular injections and readily soluble “FDDFs” are available. Ethical, juridical and methodological problems prevent controlled studies from establishing a reference in the treatment of aggression in mentally ill patients. This review summarizes the current discussion and publications on the pharmacological treatment of aggression in schizophrenic patients of the last 20 years. In addition, we will briefly present studies and case reports concerning the treatment of aggression in other psychiatric patients.
#Introduction
The etiology of human aggressive behavior is not well known. Current hypotheses do not offer any information for differentiating violent behavior in clinical populations' symptoms, causal relationships, prognosis and treatment. Aggressive syndromes can be seen in patients with the following diagnoses: organic psychoses, such as after head injuries [55], cerebral infections, metabolic diseases, drug intoxication, personality disorders such as borderline or antisocial personality disorder [43], developmental disabilities [13], dementia [18] [51], bipolar affective disorders [31] and schizophrenia [39], most often during acute psychosis [53].
The definition and use of the term aggression is not consistent - not only in clinical practice but also for research purposes. Campbell et al. [7] defines aggressive behavior as “physical attacks on other persons, on property, or on one's self (self-mutilation), with deliberate destructive intent” (p. 107). Nilsson [40] has pointed out that aggression ranges between the useful ability to get one's way and inadequate and violent pathological aggressive behavior. Therefore, one has to consider the context and the underlying values in which aggression occurs in any classification of aggression.
The main issue addressed in this review is pathological aggression, especially in schizophrenic patients. For various reasons, it is not possible to define and use the term aggression in a consistent fashion. The authors of the studies under review have interpreted the term in a relatively diverse or imprecise manner, and various methods for assessing different aspects of aggression have been used. The Epidemiologic Catchment Area (ECA) study in 1990 showed that persons with psychosis are 5 times more likely than the general population to commit violent acts [58]. Steinert et al. performed a retrospective chart examination of patients with schizophrenic or schizoaffective disorder (n = 138). They evaluated doctor's reports and staff documentation with respect to aggressive incidents such as threats, physical aggression against persons and objects, and self-directed aggression. These incidents were included if they reached a certain severity degree of aggression based on the classification of the Overt Aggression Scale for the objective rating of verbal and physical aggression (OAS) [71]. This rating scale distinguishes between verbal aggression, physical aggression against oneself, against objects, and against other people. Most of the aggressive incidents (66 %) were observed within the first week of neuroleptic treatment [57].
Unexpected, sudden aggression and violence are not necessarily manifestations of mental illness. However, if they are, public opinion often ostracizes these patients as dangerous and demands that they be hospitalized [60]. Several current epidemiological studies [58] [68] have shown a significantly higher rate of aggression in patients with mental illness. About 10% of all schizophrenic patients have been shown to suffer from various aggressive symptoms. However, it is important to consider that the great majority of mentally ill patients are not violent [3].
Noncompliance with any form of medication (new or established) often makes it difficult to find a regimen acceptable to the patient. Up to 80 % of schizophrenic patients were found to be noncompliant with their medication at least once during their illness [67]. This emphasizes the difficulty to find a medication that directly and efficiently reduces aggressive behavior without provoking disturbing side effects such as sedation, anhedonia or EPS [12] [20].
The wide variety of pharmacological substances with their many different effects on cerebral neurotransmitter systems currently in use in the treatment of aggressive behavior is symptomatic for the limited understanding of the etiology of aggression. Serotonin, dopamine, GABA, norepinephrine and other neurotransmitters are presumably involved [64], but it is not yet known which interactions between these systems regulate aggression.
Below, we will describe pharmacological substances currently used in the treatment of aggressive behavior in mostly schizophrenic patients based on MEDLINE database research for the years 1980 to 2000 using keywords such as “aggression”, “schizophrenia”, “treatment”, “pharmacological”, and “pharmacotherapy”. Later, a more specific research using special substances such as “benzodiazepines”, “haloperidol”, “clozapine” and others was carried out. About 500 publications from the last 20 years were found that discussed the therapeutic efficacy of neuroleptics and other agents in the treatment of aggression and agitation in psychiatric patients, but less than 5 % of these contain information about the treatment of aggression in schizophrenic patients. For this review, we initially used study reports directly addressing the pharmacological treatment of aggressive symptoms in schizophrenic patients only. In absence of sufficient information, only about ten articles could be included. Later on, we selected publications about the treatment of aggression in all psychiatric patients, both studies, and case reports. Preferably, we used reports including recommendations for choice and dosage of aggression-reducing agents. In addition, we will also make reference to interesting and important opinions on this topic over the last ten years.
#Antipsychotics
#Typical antipsychotics
High-potency antipsychotics such as haloperidol and others were the most commonly used and prescribed medication for the treatment of agitation and aggression in acute and active psychoses until the early 1990s [3].
These agents show sedative and antipsychotic effects in a variety of settings, and can be used easily since they are available in several galenic forms (tablets, liquids, intramuscular preparation). Obviously, the immediate antiaggressive effect is not specific or selective, but seems to be a side effect of the sedation. High-dose application (as it is often prescribed in violent schizophrenic patients) has been shown to be able to aggravate aggression [64].
As described below (see Benzodiazepines), some studies favored a combination therapy consisting, for example, of haloperidol and lorazepam, but there have also been publications showing that a monotherapy regimen with atypical neuroleptics (see respective section) or other agents was successful in the treatment of agitation and aggression in schizophrenic patients.
Mid- and low-potency antipsychotics have similar receptor affinities to high-potency agents, but a higher dose is recommended in order to achieve either therapeutic or other desired effects. Agents from this group have a more sedative effect, probably due to a higher rate of serotonin and histamine receptor blockade. Typical galenic forms are tablets and liquids; intravenous application carries an increased danger of hypotension and anticholinergic toxicity, whereas paravasal application (for example levomepromazine) may result in tissue damage. Other suggested therapy regimens combine high- and low-potency agents for a synergistic effect of sedation and treatment of other psychotic symptoms. From our MEDLINE research, there were no significant publications found in the 1980s and 1990s including psychopharmacological studies or case reports on mid- or low-potency antipsychotics.
#Atypical antipsychotics
Clozapine is a dibenzodiazepine derivate with a relatively high D1/D2 receptor affinity ratio and a receptor blockade of D4-, 5-HT1B-, H1-, 5-HT2- and α1-receptors [27].
In the last ten years, various studies (open-labeled treatment studies or retrospective chart reviews) on the effect of clozapine on hostility and aggression [4] [11] [17] [33] [46] [47] [69] have demonstrated the antiaggressive effect of clozapine. There is wide agreement about its efficacy [23]. Studies on atypical antipsychotics have shown that the reduction of aggressive behavior could not only be explained by sedation or general antipsychotic effects [63]. Based on a review of studies on the antiaggressive effect of clozapine in schizophrenic patients, Glazer and Dickson mentioned 5 possible factors responsible for the antiaggressive effect of clozapine. These factors are the decrease of psychotic symptoms, decrease of negative symptoms, the lack of EPS, the decrease in substance abuse and the decrease in suicidality [23]. A significant decrease of aggressive symptoms could be observed within the first weeks of treatment [22] [23].
Wilson [69] reported the use of clozapine in 37 longtime schizophrenic patients who showed poor or no response to neuroleptics or suffered from tardive dyskinesia. As an indicator for social functioning the number of violent episodes (assaults and self-harm) and episodes of seclusion and restraint were measured by way of reviewing medical records. Within 6 months of clozapine treatment at approximately 600 mg/day, the total number of violent episodes as well as the number of patients involved in violent episodes decreased. In parallel, the number of seclusions and restraint episodes as well as the number of patients who were secluded decreased. Ratey et al. [47] published five case reports based on a retrospective chart review of chronically schizophrenic patients with agitation and verbal aggression who were treated with clozapine in an unknown dosage for more than one year. Between 50 and 86 % fewer aggressive incidents were observed. Volavka et al. [66] observed a sample of hospitalized schizophrenic patients in an open-labeled study. The New York State Office of Mental Health had developed an assessment program with 21 hospitals participating, where 331 inpatients were treated with clozapine (DSM-III-R diagnosis of schizophrenia, treatment resistance with at least three neuroleptics in two different chemical classes). Volavka et al. found that clozapine had a significant effect on hostility, which was measured by the hostility item on the BPRS scale. To test for a selective clozapine effect on hostility, which was defined as a change of hostility that was not associated with a change in psychosis measured by the sum of four BPRS items, they performed separate analyses. Results supported the hypothesis of a selective clozapine effect [63] [66]. Rabinowitz et al. [46] published a retrospective chart review of 75 patients with persistent psychotic disorders or pervasive negative symptoms who did not respond to at least three typical neuroleptics and were hospitalized for at least 365 days in their life. Results on physical or verbal aggression were documented in the patients' charts. The number of aggressive incidents, which were defined as fear-inducing incidents requiring staff intervention, was reported. In addition, aggressive behavior and angry feelings were measured by the BPRS hostility score. Clozapine decreased incidents of physical aggression by 49 % and verbal aggression by 70 %. Hector [27] reported an open trial including 29 men treated with clozapine only or in addition to other psychopharmacological agents such as mood stabilizers or other neuroleptics. Most of these patients were in long-term hospitalization due to recurrent agitation and aggression. Most of them had been diagnosed with chronic disorganized schizophrenia with severe social impairment. Oral doses of clozapine at 250 to 600 mg were used. In the follow-up study, 24 of the 29 patients were stable and compliant with clozapine therapy. A significant reduction of threatening behavior, agitation and aggression was observed as well as an improvement in their social environment. The authors concluded that clozapine is an effective medical treatment for the target symptom of aggression in schizophrenic patients.
There have been few studies using a randomized, parallel group study design. Studies by Czobor et al. [14], Brecher et al. [2], Marder et al. [34] and Buckley et al. [5] showed an antiaggressive effect of risperidone comparable to this type of conventional antipsychotic, but with less pronounced side effects. Czobor et al. [14] treated 139 diagnosed schizophrenics in a randomized clinical trial comparing risperidone against haloperidol and placebo over 9 weeks. As patients were not chosen for aggressive behavior, this study was not representative for the purpose of this review. Antiaggressive effects (measured by the hostility item of the Positive and Negative Syndrome Scale) could be observed in patients suffering from violent behavior in acute schizophrenia. Risperidone had a better (selective) effect on hostility than did haloperidol or placebo. Using the same database as Czobor et al., Marder et al. [34] published data for 513 schizophrenic patients treated with risperidone in an 8-week randomized trial. Antiaggressive effect was measured by PANSS factor scores. Buckley et al. [5] preferred an open, case-controlled study including 27 schizophrenic or schizoaffective patients treated with risperidone against conventional antipsychotics over 6 months. Violence was measured by evaluating the use of seclusion and restraint (S&R) for the 6 month preceding and during the treatment. There was a significant reduction in aggressive behavior without any significant difference between the two treatment groups.
Demented and autistic patients are also given neuroleptics to treat aggressive behavior. In these patients suffering from agitation and behavioral disturbances, risperidone was observed to decrease symptoms of aggression [37]. McDougle et al. [37] published a 12 week double-blind, placebo-controlled trial on 31 risperidone patients with autistic disorder or pervasive developmental disorder. Aggression was rated according to SIB-Q (including self-injurious behavior and physical aggression towards others) before the trial began and after 4, 8 and 12 completed weeks of the risperidone trial. The daily dose was 2.9 ± 1.4 mg. The reduction of aggression was significant (p < 0.001). Effects began at week 4 (p < 0.02) and continued through week 8 (p < 0.009) and 12 (p < 0.01). The SID-Q score was reduced by more than 50 %. Side effects other than mild ones such as sedation were not observed.
Clozapine and the other atypicals are not yet available as intramuscular preparations, and are thus difficult to apply in managing acute aggression. Typical antipsychotics such as haloperidol or zuclopenthixol will be preferred in this case. Olanzapine, risperidone and ziprazidone will soon be available in intramuscular form, and will hopefully improve treatment possibilities for aggressive patients without inducing severe motor symptoms.
#Benzodiazepines
Benzodiazepines are often used in monotherapy regimen or in combination with other aggression reducing agents such as antipsychotics [1] [44] [56]. The advantage of benzodiazepines is their large variety of substances with very different pharmacokinetic characteristics (such as the beginning and period of effect) and their variety of preparations [41]. Benzodiazepines can be handled quite easily due to their therapeutic width [29]. Major side effects such as decreased cognition, confusion and dependency depend on dose, speed of dose augmentation, and duration of application [28] [41]. Most often, they are of minor clinical reference with regard to the treatment of acute aggression. Substances with a short half-life and no active metabolites (such as lorazepam - half-life time about 4 to 6 hours) should be preferred [50]. There have been studies, such as that of Bienik [1], which demonstrate the increased effectiveness of a lorazepam-haloperidol combined therapy compared to lorazepam alone in the treatment of agitation and aggression.
Dorevitch et al. [15] examined the efficacy of intramuscular flunitrazepam vs. intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients treated with neuroleptics. The 28 patients included in a double-blind, randomized study were either treated with 5 mg of haloperidol i. m. or 1 mg of flunitrazepam i.m. during acute aggressive outbursts. Verbal and physical aggression was measured with the Overt Aggression Scale at baseline, at 15, 30, 45, 60, 90, and 120 minutes. Compared to haloperidol, the maximum antiaggressive effect of flunitrazepam was achieved more rapidly - as early as after 30 minutes. Both agents, used as an adjunct to the existing neuroleptic treatment, were found to be similarly effective in controlling agitated and aggressive behavior in acute psychosis.
Other authors have also suggested haloperidol and benzodiazepines (here given intravenously in combination) acting synergistically [16] [24].
There is also evidence that benzodiazepines are effective in the treatment of aggression in patients with a bipolar disorder. Lenox et al. [31] published a randomized, double-blind clinical study of lorazepam versus haloperidol in 20 hospitalized patients with a DSM-III-R diagnosis of bipolar disorder, concomitantly being treated with lithium. Lithium was administered daily to all patients with a dosage achieving serum levels of 0.5 to 0.75 mmol/l. Lorazepam or haloperidol were added in daily doses of 8.8 ± 4.2 mg and 12.7 ± 3.2 mg, respectively, for 14 days. Patients in both treatment groups responded within one week with a mean reduction of manic symptoms by about 60 %. Lenox concluded that lorazepam was an efficacious and safe alternative to haloperidol as an adjunctive treatment to lithium in manic agitation.
Views held in recent publications on the use of benzodiazepines are not unanimous. Recommendations vary from strict refusal to short-time use alone or in combination with other agents. They all agree on a restricted use for acute patients only. Long-term medication, necessary in chronic schizophrenic patients, should be composed of other substances due to the side effects mentioned above.
#Mood stabilizers
Lithium has been reported to have antiaggressive effects and to be especially effective in the treatment of aggressive-impulsive behavior. The mechanism of the antiaggressive effect of lithium is not yet clear. Under discussion is that its serotonergic properties are responsible for its antiaggressive effects. This effect could also be due to a reduction of catecholaminergic function [40]. No publications on specific use of lithium in aggression treatment, especially in schizophrenic patients, could be found in the MEDLINE database from the years 1980 to 2000. There are some articles from the 1980s and early 1990s, such as Elphick [19], on combination therapy with lithium with other agents, mainly with carbamazepine. All these publications referred to the pharmacological treatment of agitation and aggression in dementia, mental retardation or cerebral organic diseases such as frontal lobe damage and genetic disorders. Combination therapy with carbamazepine and lithium is often recommended, for example by Fritze [21]. However, a specific study on this combination in schizophrenic patients could not be found. Only one case report [6] on a patient with repetitive aggression in chronic schizophrenia described a positive outcome with this combination therapy.
Nilsson described four main areas in which lithium is used and systematically evaluated in the treatment of pathological aggression. She names the treatment of psychiatric disorders of the adult, the treatment of aggression in conduct an emotional disorders beginning in childhood and adolescence, the treatment of aggression in mentally retarded patients and the specific use in the treatment of impulsive behavior [40].
Nilsson pointed out that clinical studies on the effect of lithium in the therapy of aggression in adults with a psychiatric disorder often investigate those individuals who have already had a history of treatment resistance. The efficacy of lithium in this indication was not the main purpose of these studies, and their relevance is therefore limited [40]. The antiaggressive effect of lithium in treating mentally retarded patients has been explored more extensively explored. Lithium is given to control impulsive aggressive episodes and to treat self-mutilation usually observed in these patients [7]. Tyrer et al. published a double-blind placebo-controlled study comparing the effect of lithium and placebo as add-on medication. They treated 25 mentally handicapped inpatient adults with persistent aggressive behavior for five months. All of them received neuroleptic or anticonvulsant medication. Aggression was measured by rating scales and by documentation of seclusion episodes and accident reports. They found a significant improvement of aggression during lithium medication. No toxic effects of the lithium medication occurred [61].
Especially Campbell et al. conducted a number of studies on the antiaggressive effect of lithium in the treatment of children with conduct disorder. In a randomized pilot study 1982, they assessed the efficacy of lithium, haloperidol and chlorpromazine in 15 inpatient children between 6 and 12 years who showed chronic aggressive and explosive behavior. They used behavioral ratings: Children's Psychiatric Rating Scale (CPRS), Clinical Global Impressions (CGI), Conners' Parent Teacher Questionnaire (PTQ), and a scale of side effects. All groups improved in aggressive behavior on the optimal medication dosage. No significant differences among the three drug groups were observed, but chlorpromazine led to extreme sedation [7]. In 1984, Campbell et al. conducted a double-blind controlled study in 61 treatment-resistant hospitalized children aged 5 to 13 with a diagnosed aggressive conduct disorder subtype. They were treated with haloperidol, lithium or placebo for four weeks. Diverse behavioral measures - CPRS, CGI, PTQ and others, as well as a scale of side effects - were used. Haloperidol and lithium led to a significant reduction in hyperactivity, aggression, and hostility, but haloperidol induced more side effects [8]. In 1995, Campbell et al. again examined the efficacy of lithium in the therapy of 50 treatment-refractory children between 5 to 12 years of age diagnosed with conduct disorder, under-socialized aggressive type. In this double-blind, placebo-controlled study, children were given lithium or placebo treatment for 6 weeks. Lithium was superior to placebo but the effects were more modest compared with the previous study [10].
Carbamazepine (CBZ) has been shown to exert presynaptic, but not postsynaptic effects upon noradrenergic and serotonergic neurons. A direct action on adenosine receptors is evident, maybe as an antagonist. Adenosine itself has modulatory effects upon a variety of neurotransmitters including 5-HT catecholamines [48].
In 1984, Luchins [32] reported about six schizophrenic patients with aggressive episodes who had received a six-week course of carbamazepine (CBZ) in addition to other neuroleptic medication. Aggression was significantly reduced (p < 0.05). A Japanese double-blind study published in 1989 [42] also showed CBZ to be effective in the treatment of persistent aggression in patients with schizophrenia and schizoaffective disorder. 162 patients were treated four weeks with neuroleptics plus carbamazepine vs. plus placebo. The target symptom - “excited state” - was assessed on a 5-point rating scale. The sum of patients with moderate and marked improvement was significantly higher in the group that received neuroleptics in combination with CBZ. No recent studies on this topic could be found.
Lemke [30] evaluated the CBZ treatment (200 - 600 mg daily) in an open study in 29 old-age psychiatric patients mainly with progressive dementia-related disorders suffering from agitated and aggressive behavior. In 81 % of the patients, CBZ was effective in reducing agitation and affective disorders.
There is only limited information on valproic acid as an aggression-reducing agent, such as by Wroblewski [70]. In a review article by Grossman [26], valproate was mentioned as being effective in the treatment of aggression in demented patients.
#SSRIs
The antidepressive effect of the serotonin reuptake inhibitors (SSRIs) is based on the augmentation of serotonin transmission in the CNS following the uptake inhibition. Several psychopathological symptoms such as aggression, anxiety, and depressed mood seem to be correlated to a reduced brain serotonin metabolism [59]. Some studies of the early 1990s referred to the (effective) SSRI treatment of psychotic patients and personality disorders (borderline, schizotypal).
There are very few publications about SSRI treatment of aggressive syndromes in schizophrenic patients.
Vartiainen et al. conducted the first randomized double-blind study on the treatment of aggressive behavior in chronically violent schizophrenic inpatients in 1995 [62]. They used citalopram as the most specific SSRI available at that time in a dosage of between 20 and 60 mg per day in addition to neuroleptic medication during a 24-week period. Aggression was assessed with a modified Staff Observation Aggression Scale (SOAS), Social Dysfunction and Aggression Scale (SDAS) and Global Aggression Scale (GAS). There was no statistically significant difference in the severity of aggressive incidents in SOAS (p = 0.52), but their frequency decreased during citalopram medication (p = 0.027). GAS values were not significantly different between the two groups; SDAS scores were slightly lower (p = 0.16) during citalopram treatment. The study's authors admitted several comparative problems and a rather small group size of 14 patients. Thus, this study does not carry general validity.
Markovitz et al. [35] examined patients with borderline or schizotypal personality disorder in a prospective, non-blind 12-week trial of 80 mg of fluoxetine. 12 of the 22 patients reported self-mutilating behavior prior to the study. Self-aggression was reduced by 97 % at the end of the study. A double-blind, placebo-controlled study of the SSRI fluvoxamine in the treatment of aggression in adults with autistic disorder [38] showed no statistically relevant effect on aggression.
#Beta-blockers
Beta-blockers are agents primarily used in the treatment of hypertension, but have also been shown to reduce symptoms of aggression in patients with a variety of basic psychiatric or neurological disorders such as mentally retarded [49], brain injury, or chronic schizophrenia. Severe side effects such as hypotension and bradycardia have to be mentioned [52].
Sorgi et al. [45] [54] showed nadolol to be useful in treating aggression in patients with chronic schizophrenia. The authors conducted a retrospective chart review of seven patients with chronic schizophrenia and aggressive behavior. Chronic aggressive behavior was defined as a history of episodes of physical or verbal assault behavior. The number of aggressive behaviors and the extent of restriction needed for the safe containment of the patients were documented. Six of seven patients showed an improvement in aggressive behavior [54].
Our MEDLINE research turned up just one placebo-controlled double-blind study [25], a study on treating patients with an organic brain disease with propanolol (200 to 520 mg daily). At least one month of treatment was necessary. Afterwards, 10 times fewer episodes of assault behavior were reported. Another prospective study [36] that compared effects of beta-blockers and CBZ recommended both substances as being helpful in the treatment of repetitive aggression.
#Other agents
There were some other agents used to treat aggression and agitation such as 5-hydroxy-tryptophan, agonists to 5-HT1-receptors (such as eltoprazine) or cyproterone acetate [56]. However, there are just one or two case reports about these agents in recent literature.
#Conclusions
The numerous psychopharmacologic treatment recommendations for combating aggression and agitation in schizophrenic patients reflect the low level of knowledge about the neurobiological basis of aggression. Nearly all substance classes used in mentally ill people have been prescribed with rather varied results.
Although acute management of typical symptoms of psychosis such as disturbances of thoughts, anxiety and hallucinations has more difficult since “modern” atypical antipsychotics have become available, aggression is still a significant and severe problem. Management of aggression still remains difficult, not only because no substance has an established indication for its treatment.
Due to the inhomogeneous definition of the target symptom and the various and often inadequate methods of assessing aggressive behavior, the comparability of the efficacy of different pharmacological substances is hindered. There is no broad basis on which clinicians can base their choice of different substances in the treatment of aggression. Only few studies have been designed as randomized, double-blind studies. Methodological problems that reduce the ability to generalize most of the reviewed findings are obvious. Non-representative patient samples as a result of biased selection, lack of adequate control groups, and ignorance to additional medication and comorbidity are factors that diminish the validity of these results. Especially in the antiaggressive treatment of schizophrenia, it is necessary to test for a selective drug effect on aggression that is independent of changes in general psychopathology.
Nevertheless, it is possible to draw some basic conclusions from publications reviewed in this article:
Typical high-potency neuroleptics and benzodiazepines, preferably used in combination and intravenously, are indicated for the short-time treatment of aggression and agitation in patients with acute psychosis or schizophrenia. No severe side effects were seen using these agents for this indication and in the regimen mentioned.
Repetitive aggression in patients with chronic schizophrenia demands other forms of medication. In patients compliant with an oral form of substance application, atypical antipsychotics with a preference for clozapine (for which study results show the greatest efficacy) should be used. As atypical neuroleptics are not available as depot preparations, noncompliant patients who need to be managed in the long-term still have to be treated with intramuscular injections of (high-potency) neuroleptics. However, one always has to bear in mind the possible severe and partly non-reversible side effects such as tardive dyskinesia. Other specific demands on the management of aggression are to avoid polypharmacy and high doses of neuroleptics (always use the lowest effective dose of medication!) to protect the actual patient and other patients and to guarantee good sleep hygiene.
There is an urgent need to refine the treatment of aggression on the basis of specific studies to be done in the future.
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- 31 Lenox R H, Newhouse P A, Creelman W L, Whitacker T M. Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psych. 1992; 53 47-52
- 32 Luchins D J. Carbamazepine in violent non-epileptic schizophrenics. Psychopharmacology Bulletin. 1984; 20 (3) 569-571
- 33 Mallya A R, Roos P D, Roebuck-Colgan K. Restraint, seclusion, and clozapine. J Clin Psych. 1992; 53 395-397
- 34 Marder S R, Davis J M, Chouinard G. The effects of rsiperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trial. Jour Clin Psych. 1997; 58 (12) 538-546
- 35 Markovitz P J, Calabrese J R, Schulz S C, Meltzer H Y. Fluoxetine in the treatment of borderline and schizotypal personality disorder. Am J Psych. 1991; 148 1064-1067
- 36 Mattes J A. Carbamazepine vs. propanolol for rage outbursts. Psychopharmacol Bull. 1988; 24 179-182
- 37 McDougle C J, Homes J P, Carlson D C. A double-blind placebo controlled study of rsiperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psych. 1998; 55 633-641
- 38 McDouble C J, Naylor S T, Cohen D J, Volkmar F R, Heninger G R, Price L H. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry. 1996; 53 1001-1008
- 39 Morrison E F. A hierachy of aggressive and violent behaviors among psychiatric inpatients. Hosp Comm Psych. 1992; 43 505-506
- 40 Nilsson A.
Lithium in der Therapie und Prophylaxe pathologischer Aggression. In: Müller-Oerlinghausen B (ed) Die Lithiumtherapie: Nutzen, Risiken, Alternativen. Berlin; Springer 1997: 278-289 - 41 Nissen G, Fritze J, Trott G E.
Psychopharmaka im Kindes- und Jugendalter. Ulm, Stuttgart, Jena, Lübeck; Fischer 1998 - 42 Okuma T, Yamashita I, Takahashi R. A double-blind study of adjunctive carbamazepine versus placebo on excited states of schizophrenia and schizoaffective disorders. Acta Psychiatr Scand. 1989; 80 250-259
- 43 Pabis D J, Stanislaw S W. Pharmacotherapy of aggressive behavior. Ann Pharmacother. 1996; 30 278-287
- 44 Pilowsky L S, Ring H, Shine P J, Battersby M, Lader M. Rapid tranquillisation - a survey of emergency prescribing in a general psychiatric hospital. Br J Psych. 1992; 160 831-835
- 45 Polakoff S A, Sorgi P J, Ratey J J. The treatment of impulsive and aggressive behavior with nadolol. J Clin Psychopharmacol. 1996; 6 125-126
- 46 Rabinowitz J, Avnon M, Rosenberg V. Effect of clozapine on physical and verbal aggression. Schizophr Res. 1996; 22 249-255
- 47 Ratey J J, Leveroni C, Kilmer D. The effects of clozapine on severely aggressive psychiatric inpatients in a state hospital. J Clin Psych. 1993; 54 219-223
- 48 Rittmannsberger H. Carbamazepin in der Behandlung psychischer Erkrankungen: Wirkungen und Nebenwirkungen. Wiener Med Woch. 1990; 15 398-404
- 49 Ruedrich S L, Grush L, Wilson J. Beta adrenergic blocking medications for aggressive and self-injurious mentally retarded persons. Am J Mental Retard. 1990; 95 110-119
- 50 Salzman C, Solomon D, Miyawaki E, et al. Parenteral lorazepam versus parenteral haloperidol for the control of psychiatric disorder behavior. J Clin Psych. 1991; 52 177-180
- 51 Schneider L S, Sobin P B. Non-neuroleptic treatment of behavioral symptoms and agitation in Alzheimer's disease and other dementia. Psychopharm Bull. 1992; 28 71-79
- 52 Sheppard G P. High-dose propanolol in schizophrenia. Br J Psych. 1979; 134 470-476
- 53 Silver H, Kushnir M. Treatment of aggression in schizophrenia. Br J Psych. 1998; 155 1298
- 54 Sorgi P J, Ratey J J, Polakoff S. Beta-adrenergic blockers for the control of aggressive behavior in patients with chronic schizophrenia. Am J Psych. 1986; 143 775-776
- 55 Stanislaw S. Neuere Tendenzen in der Pharmakotherapie aggressiven Verhaltens bei psychisch Kranken. Fortschr Neurol Psychiatr. 1992; 60 393-400
- 56 Steinert T. Neuere Tendenzen in der Pharmakotherapie aggressiven Verhaltens bei psychisch Kranken. Fortschr Neurol Psychiatr. 1992; 60 393-400
- 57 Steinert T, Sippach T, Gebhardt R P. How common is violence in schizophrenia despite neuroleptic treatment?. Pharmacopsych. 2000; 33 98-102
- 58 Swanson J, Holzer C, Ganju V. volence and psychiatric disorder in the community: evidence from the Epidemiologic Catchment area surveys. Hosp Comm Psych. 1990; 41 761-770
- 59 Tauscher J, Kasper S. Sertralin - selektiver Serotonin-Wiederaufnahmehemmer mit geringem Interaktionsprofil. Fundamenta Psychiatrica. 1997; 11 179-189
- 60 Taylor P J.
Schizophrenia and crime: distinctive patterns in association. In: Hodgins S (ed) Crime and mental disorder. Newbury Park, CA USA; Sage Publications 1993 - 61 Tyrer S P, Walsh A, Edwards D E, Berney T P, Stephens D A. Factors associated with a good response to lithium in aggressive mentally handicapped subjects. Prog Neuropsychopharmacol. 1984; 8 751-755
- 62 Vartiainen H, Tiihonen J, Putkonen A, Koponen H, Virkkkunen M, Hakola P. Citalopram, a selective serotinin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scan. 1995; 91 348-351
- 63 Volavka J. The effects of clozapine on aggression and substance abuse in schizophrenic patients. J Clin Psych. 1999; 60 (12) 43-46
- 64 Volavka J.
The neurobiology of violence. Washington DC, USA; Am Psych Press 1995 - 65 Volavka J, Citrome L. Atypical antipsychotics in the treatment of persistently aggressive psychotic patients: methodological concerns. Schizophrenia Res. 199; 35 S23-S33
- 66 Volavka J, Zito J M, Vitrai J, Czobor P. Clozapine effects on hostility and aggression in schizophrenia. J Clin Psychopharmacol. 1993; 13 287-289
- 67 Weiden P J, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995; 21 419-429
- 68 Wessely S. the epidemiology of crime, violence and schizophrenia. Br J Psych. 1997; 170 (32) 8-11
- 69 Wilson W H. Clinical review of clozapine treatment in a state hospital. Hosp comm Psych. 1992; 43 700-703
- 70 Wroblewski B A, Joseph A B, Kupfer J, Kalliel K. Effectiveness of valproic acid on destructive and aggressive behaviors in patients with acquired head injury. Brain Inj. 1997; 11 37-47
- 71 Yudofsky S C, Silver J M, Jackson W, Endicott J, Williams D. The overt aggression scale for the objective rating of verbal and physical aggression. Am J Psychiatry. 1986; 143 35-39
- 72 Yudofsky S C, Silver J M, Hales R E. Pharmacologic management of aggression in the elderly. J Clin Psych. 1990; 51 (10) 22-28
Prof. Dr. med. Dieter Naber
Department of Psychiatry and Psychotherapy, University Hospital Eppendorf
Martinistraße 52
20246 Hamburg
Germany
Phone: + 49-40-42803-2231
Fax: + 49-40-42803-9135
References
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- 29 Laux G, Dietmeier O, König W.
Psychopharmaka - ein Leitfaden. 5. Aufl. Ulm, Stuttgart, Jena, New York; Fischer 1995 - 30 Lemke M R, Stuhlmann W. Therapeutische Anwendung von Carbamazepin bei Antriebssteigerung und Affektstörungen gerontopsychiatrischer Patienten. Psychiatrische Praxis. 1994; 21 147-150
- 31 Lenox R H, Newhouse P A, Creelman W L, Whitacker T M. Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psych. 1992; 53 47-52
- 32 Luchins D J. Carbamazepine in violent non-epileptic schizophrenics. Psychopharmacology Bulletin. 1984; 20 (3) 569-571
- 33 Mallya A R, Roos P D, Roebuck-Colgan K. Restraint, seclusion, and clozapine. J Clin Psych. 1992; 53 395-397
- 34 Marder S R, Davis J M, Chouinard G. The effects of rsiperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trial. Jour Clin Psych. 1997; 58 (12) 538-546
- 35 Markovitz P J, Calabrese J R, Schulz S C, Meltzer H Y. Fluoxetine in the treatment of borderline and schizotypal personality disorder. Am J Psych. 1991; 148 1064-1067
- 36 Mattes J A. Carbamazepine vs. propanolol for rage outbursts. Psychopharmacol Bull. 1988; 24 179-182
- 37 McDougle C J, Homes J P, Carlson D C. A double-blind placebo controlled study of rsiperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psych. 1998; 55 633-641
- 38 McDouble C J, Naylor S T, Cohen D J, Volkmar F R, Heninger G R, Price L H. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry. 1996; 53 1001-1008
- 39 Morrison E F. A hierachy of aggressive and violent behaviors among psychiatric inpatients. Hosp Comm Psych. 1992; 43 505-506
- 40 Nilsson A.
Lithium in der Therapie und Prophylaxe pathologischer Aggression. In: Müller-Oerlinghausen B (ed) Die Lithiumtherapie: Nutzen, Risiken, Alternativen. Berlin; Springer 1997: 278-289 - 41 Nissen G, Fritze J, Trott G E.
Psychopharmaka im Kindes- und Jugendalter. Ulm, Stuttgart, Jena, Lübeck; Fischer 1998 - 42 Okuma T, Yamashita I, Takahashi R. A double-blind study of adjunctive carbamazepine versus placebo on excited states of schizophrenia and schizoaffective disorders. Acta Psychiatr Scand. 1989; 80 250-259
- 43 Pabis D J, Stanislaw S W. Pharmacotherapy of aggressive behavior. Ann Pharmacother. 1996; 30 278-287
- 44 Pilowsky L S, Ring H, Shine P J, Battersby M, Lader M. Rapid tranquillisation - a survey of emergency prescribing in a general psychiatric hospital. Br J Psych. 1992; 160 831-835
- 45 Polakoff S A, Sorgi P J, Ratey J J. The treatment of impulsive and aggressive behavior with nadolol. J Clin Psychopharmacol. 1996; 6 125-126
- 46 Rabinowitz J, Avnon M, Rosenberg V. Effect of clozapine on physical and verbal aggression. Schizophr Res. 1996; 22 249-255
- 47 Ratey J J, Leveroni C, Kilmer D. The effects of clozapine on severely aggressive psychiatric inpatients in a state hospital. J Clin Psych. 1993; 54 219-223
- 48 Rittmannsberger H. Carbamazepin in der Behandlung psychischer Erkrankungen: Wirkungen und Nebenwirkungen. Wiener Med Woch. 1990; 15 398-404
- 49 Ruedrich S L, Grush L, Wilson J. Beta adrenergic blocking medications for aggressive and self-injurious mentally retarded persons. Am J Mental Retard. 1990; 95 110-119
- 50 Salzman C, Solomon D, Miyawaki E, et al. Parenteral lorazepam versus parenteral haloperidol for the control of psychiatric disorder behavior. J Clin Psych. 1991; 52 177-180
- 51 Schneider L S, Sobin P B. Non-neuroleptic treatment of behavioral symptoms and agitation in Alzheimer's disease and other dementia. Psychopharm Bull. 1992; 28 71-79
- 52 Sheppard G P. High-dose propanolol in schizophrenia. Br J Psych. 1979; 134 470-476
- 53 Silver H, Kushnir M. Treatment of aggression in schizophrenia. Br J Psych. 1998; 155 1298
- 54 Sorgi P J, Ratey J J, Polakoff S. Beta-adrenergic blockers for the control of aggressive behavior in patients with chronic schizophrenia. Am J Psych. 1986; 143 775-776
- 55 Stanislaw S. Neuere Tendenzen in der Pharmakotherapie aggressiven Verhaltens bei psychisch Kranken. Fortschr Neurol Psychiatr. 1992; 60 393-400
- 56 Steinert T. Neuere Tendenzen in der Pharmakotherapie aggressiven Verhaltens bei psychisch Kranken. Fortschr Neurol Psychiatr. 1992; 60 393-400
- 57 Steinert T, Sippach T, Gebhardt R P. How common is violence in schizophrenia despite neuroleptic treatment?. Pharmacopsych. 2000; 33 98-102
- 58 Swanson J, Holzer C, Ganju V. volence and psychiatric disorder in the community: evidence from the Epidemiologic Catchment area surveys. Hosp Comm Psych. 1990; 41 761-770
- 59 Tauscher J, Kasper S. Sertralin - selektiver Serotonin-Wiederaufnahmehemmer mit geringem Interaktionsprofil. Fundamenta Psychiatrica. 1997; 11 179-189
- 60 Taylor P J.
Schizophrenia and crime: distinctive patterns in association. In: Hodgins S (ed) Crime and mental disorder. Newbury Park, CA USA; Sage Publications 1993 - 61 Tyrer S P, Walsh A, Edwards D E, Berney T P, Stephens D A. Factors associated with a good response to lithium in aggressive mentally handicapped subjects. Prog Neuropsychopharmacol. 1984; 8 751-755
- 62 Vartiainen H, Tiihonen J, Putkonen A, Koponen H, Virkkkunen M, Hakola P. Citalopram, a selective serotinin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scan. 1995; 91 348-351
- 63 Volavka J. The effects of clozapine on aggression and substance abuse in schizophrenic patients. J Clin Psych. 1999; 60 (12) 43-46
- 64 Volavka J.
The neurobiology of violence. Washington DC, USA; Am Psych Press 1995 - 65 Volavka J, Citrome L. Atypical antipsychotics in the treatment of persistently aggressive psychotic patients: methodological concerns. Schizophrenia Res. 199; 35 S23-S33
- 66 Volavka J, Zito J M, Vitrai J, Czobor P. Clozapine effects on hostility and aggression in schizophrenia. J Clin Psychopharmacol. 1993; 13 287-289
- 67 Weiden P J, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995; 21 419-429
- 68 Wessely S. the epidemiology of crime, violence and schizophrenia. Br J Psych. 1997; 170 (32) 8-11
- 69 Wilson W H. Clinical review of clozapine treatment in a state hospital. Hosp comm Psych. 1992; 43 700-703
- 70 Wroblewski B A, Joseph A B, Kupfer J, Kalliel K. Effectiveness of valproic acid on destructive and aggressive behaviors in patients with acquired head injury. Brain Inj. 1997; 11 37-47
- 71 Yudofsky S C, Silver J M, Jackson W, Endicott J, Williams D. The overt aggression scale for the objective rating of verbal and physical aggression. Am J Psychiatry. 1986; 143 35-39
- 72 Yudofsky S C, Silver J M, Hales R E. Pharmacologic management of aggression in the elderly. J Clin Psych. 1990; 51 (10) 22-28
Prof. Dr. med. Dieter Naber
Department of Psychiatry and Psychotherapy, University Hospital Eppendorf
Martinistraße 52
20246 Hamburg
Germany
Phone: + 49-40-42803-2231
Fax: + 49-40-42803-9135