Hostility in schizophrenia: An integrated analysis of the combined Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the European First Episode Schizophrenia Trial (EUFEST) studies.

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enrolled a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) enrolled 498 patients. We have combined these two samples to study the effects of hostility on study discontinuation as well as to examine correlates and predictors of hostility. Individual data from 1154 patients with complete data were used for analyses. Survival analysis demonstrated that higher hostility was associated with earlier all-cause treatment discontinuation. Furthermore, regression analysis indicated that increased hostility was associated with more severe positive symptoms, lower adherence to pharmacological treatment, younger age, impaired insight, and more drug or alcohol consumption. The clinical implications of the results point to the importance of establishing therapeutic alliance while managing patient's symptoms of hostility with antipsychotics such as olanzapine combined with psychosocial interventions to improve insight and reduce substance use.

Heterogeneity of violence in schizophrenia and implications for long-term treatment.

AIMS: Most patients with schizophrenia are not violent. However, persistent violent behaviour in a minority of patients presents a therapeutic challenge. Published treatment guidelines and most pharmacological and epidemiological literature on violence in schizophrenia treat overt physical aggression as a homogeneous phenomenon. The aim of this review is to address the subtyping of violent behaviour in schizophrenia, and to relate the subtypes to treatment. METHOD: Literature describing subtypes of violence in schizophrenia and the treatment of this problem was reviewed. 'Schizophrenia', 'violence', 'aggression', 'hostility' and 'personality disorders' were the principal search terms describing behaviours. Generic names of individual atypical antipsychotics and mood stabilisers were used in treatment searches. RESULTS: There are at least three aetiological subtypes of violence in schizophrenia (i) that related directly to positive psychotic symptoms, (ii) impulsive violence and (iii) violence stemming from comorbidity with personality disorders, particularly psychopathy. Current treatment of violence in schizophrenia relies on antipsychotics and mood stabilisers. The evidence of effectiveness is relatively strong for clozapine, but inconsistent for other treatments. No systematic recommendations relating the treatment to aetiological subtypes of violence were found. DISCUSSION: The inconsistent effectiveness of the current treatments of violent behaviour in schizophrenia is due, at least in part, to the aetiological heterogeneity of that behaviour. We should not expect that any given pharmacological treatment will be equally effective in reducing violent behaviour caused by psychosis, impaired impulse control or personality disorder. CONCLUSION: Violence in schizophrenia is aetiologically heterogeneous. This heterogeneity has therapeutic implications that impact clinical practice today and should be further explored in future studies.

Update on the biological treatment of aggression.

This review is focused on aggressive behavior in adult patients with major mental disorders. Aggression, agitation, and hostility are defined. The roles of intramuscular forms of ziprasidone and olanzapine in the treatment of acute agitation and aggression are discussed. We review general considerations pertaining to persistent aggression in inpatients and outpatients, including comorbidity of major mental disorders with substance use disorders and personality disorders. The role of clozapine as an antiaggressive agent is well established, particularly in inpatients. Evidence also exists for the efficacy of risperidone, olanzapine, quetiapine, and aripiprazole. Anticonvulsants and lithium are widely used with the intent to control aggression, but their efficacy lacks strong evidential support. Benzodiazepines have a role in controlling acute agitation, but their long-term use for persistent aggression is not recommended. There is evidence for antiaggressive effects of SSRIs and hormonal agents with antiandrogenic properties. Beta-adrenergic blockers and electroconvulstive treatment are rarely used in clinical practice to control aggression, but they may be effective. The heterogeneity of aggressive behavior is a challenge for developing rational treatments. Emerging genetic findings hold a promise of future treatments of aggressive behavior developed on the basis of individual patients' genotypes.

Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.

OBJECTIVE: This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. METHODS: A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). RESULTS: Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. CONCLUSION: Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.

Haloperidol blood levels in acute mania with psychosis.

In this study, the authors examined the relationship between steady-state haloperidol blood levels and clinical response in patients with acute psychotic mania. Fifty-four inpatients with acute mania were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg/day. Each subject also received a concomitant medication: lorazepam 4 mg/day, lithium, or placebo. The relationship between steady-state haloperidol blood levels and clinical improvement was studied using analysis of covariance. There was wide interindividual variation in the haloperidol blood level-dose ratio. Haloperidol blood levels (log-transformed) were found to significantly correlate with clinical response in acute mania. Low-dose haloperidol with concomitant lithium may produce an optimal response in acute mania. Haloperidol blood levels may be clinically useful in identifying patients who are nonresponsive because of low drug levels and, hence, in enhancing optimal haloperidol dosing for acute mania with psychosis.

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial.

The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04; p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.

IQ scores of treatment-resistant schizophrenia patients before and after the onset of the illness.

In this study we examined the correlations of actual pre-morbid IQ scores (obtained from routine educational assessments) and estimated current IQ scores in 27 treatment-resistant schizophrenia patients. Pre-morbid (mean = 93) and current (mean = 83) IQ scores were significantly correlated (r = 0.807, P < 0.0001), while duration of illness (10-40 years) was unrelated to the magnitude of IQ score decline (r = -0.103, P = 0.575). These data suggest that pre-morbid IQ test scores are highly predictive of post-morbid scores.

Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior.

Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (chi(2) = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1-8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior.

High-dose treatment with haloperidol: the effect of dose reduction.

High doses of antipsychotic medications are sometimes prescribed in clinical practice, although the efficacy and safety of such treatment have not been established. The purpose of this study was to determine whether high-dose, long-term antipsychotic treatment prescribed on the basis of clinical judgment can be justified. Patients who were receiving high doses of haloperidol were screened, and those patients whose plasma levels were at least 15 ng/mL were randomly assigned to an experimental group (N = 11) or to a control group (N = 12). The experimental group underwent a dose reduction to achieve the target plasma level of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control group treatment was maintained at the original level. Both groups were then followed up for another 16 weeks, during which the plasma levels of haloperidol were kept constant. The study used double-blind procedures. Both groups showed an average slight symptom reduction. There was no significant difference in the severity of symptoms between the two groups at any time point. The dose reduction had no apparent adverse effects. Thus, the results of this study did not provide justification for high-dose, long-term antipsychotic treatment. However, these results must be interpreted with caution because the sample studied here was small and biased.

An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder.

Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.

Suicidal behavior in patients with schizophrenia is related to COMT polymorphism.

A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients.

Acute mania: haloperidol dose and augmentation with lithium or lorazepam.

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.

Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior.

A common 44-base pair insertion/deletion polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been observed to be associated with affective illness and anxiety-related traits. This biallelic functional polymorphism, designated long (L) and short (S), affects 5-HTT gene expression since the S promoter is less active than the L promoter. Since there is strong evidence of a disturbance in brain serotonergic transmission among antisocial, impulsive, and violent type 2 alcoholic subjects, we decided to test the hypothesis that the frequency of the S allele, which is associated with reduced 5-HTT gene expression, is higher among habitually violent type 2 alcoholics when compared with race and gender-matched healthy controls and non-violent late-onset (type 1) alcoholics. The 5-HTT promoter genotype was determined by a PCR-based method in 114 late onset (type 1) non-violent alcoholics, 51 impulsive violent recidivistic offenders with early onset alcoholism (type 2), and 54 healthy controls. All index subjects and controls were white Caucasian males of Finnish origin. The S allele frequency was higher among type 2 alcoholics compared with type 1 alcoholics (chi2 = 4.86, P = 0.028) and healthy controls (chi2 = 8.24, P = 0.004). The odds ratio for SS genotype vs LL genotype was 3.90, 95% Cl 1.37-11.11, P = 0.011 when type 2 alcoholics were compared with healthy controls. The results suggest that the 5-HTT 'S' promoter polymorphism is associated with an increased risk for early onset alcoholism associated with antisocial personality disorder and impulsive, habitually violent behavior.

The neurobiology of violence: an update.

Clinical correlates of violent behavior are known, but the underlying mechanisms are not well understood. This article reviews recent progress in the understanding of such mechanisms involving complex interactions between genes, prenatal and perinatal environmental factors, and rearing conditions. Violent behavior is heterogeneous; that is, impulsive and premeditated violent acts differ in their origins, mechanisms, and management. Recent molecular genetic studies of neurotransmitter regulation are providing new insights into pathophysiology of violent behavior. Functional anatomy of neurotransmitters involved in the regulation of violent behavior is being studied with recently developed brain imaging methods. Increasing evidence indicates commonalities between the neurobiology of violent and suicidal behavior. Progress in the prevention and management of violent behavior depends on studies that address biological factors in their social context. This article updates a previous review.

Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism.

Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine. It has been suggested that a common functional genetic polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT enzyme activity, may contribute to the etiology of mental disorders such as bipolar disorder and alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it is conceivable that subjects who inherit the allele encoding the low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. The aim of this study was to test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism was determined in two independent male late onset (type 1) alcoholic populations in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT genotype and allele frequencies were compared with previously published data from 3140 Finnish blood donors (general population) and 267 race- and gender-matched controls. The frequency of low activity allele (L) was markedly higher among the patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with the general population. When all patients were compared with the general population (blood donors), the difference was even more significant (P = 0.0004). When genotypes of all alcoholics (n = 123) were compared with genotypes of matched controls, the odds ratio (OR) for alcoholism for those subjects having the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22-5.19, P = 0.006. Also, L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiological (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3-25.7%). The results indicate that the COMT polymorphism contributes significantly to the development of late-onset alcoholism.

Psychopathy and violent behavior among patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Although a strong association between violence and psychopathy has been demonstrated in nonpsychotic forensic populations, the relationship between psychopathy and violence among patients with schizophrenia has not been thoroughly explored. Patients with and without a history of persistent violent behavior were compared for comorbidity of psychopathy and schizophrenia or schizoaffective disorder. METHODS: Violent and nonviolent patients were identified through reviews of hospital charts and records of arrests and convictions. The Psychopathy Checklist: Screening Version was administered to 51 patients, 26 violent patients and 25 matched nonviolent patients. Analysis of variance was used as the principal statistical method for comparing violent and nonviolent groups. RESULTS: Mean psychopathy scores were higher for violent patients than nonviolent patients. Five of the violent patients (19 percent) had scores exceeding the cutoff for psychopathy, and 13 (50 percent) scored in the possible psychopathic range. All of the nonviolent patients scored below the cutoff for possible psychopathy. Higher psychopathy scores were associated with earlier age of onset of illness and more arrests for both violent and nonviolent offenses. CONCLUSIONS: The comorbidity of schizophrenia and psychopathy was found to be higher among violent patients than among nonviolent patients. Violent patients with schizophrenia who score high on measures of psychopathy may have a personality disorder that precedes the emergence of psychotic symptoms, or they may constitute a previously unclassified subtype of schizophrenia, characterized by early symptoms of conduct disorder symptoms and persistent violent behavior.

The effects of clozapine on aggression and substance abuse in schizophrenic patients.

Aggressive behavior in schizophrenic patients, although infrequent, is a serious problem. It is, however, a relatively common reason for psychiatric admission and poses an increasing threat as more patients are cared for in the community. There is a strong association between substance abuse and violent behavior, and comorbid substance abuse in schizophrenia is also a major problem. The recent introduction of the atypical antipsychotics has brought hope for the pharmacologic management of this group of patients. These newer agents are thought to have antiaggressive effects and perhaps decrease cravings for illicit substances and alcohol. Data from a number of studies have demonstrated that clozapine has antiaggressive effects. A retrospective analysis of 331 schizophrenic patients assessed the effects of clozapine on hostility and aggression. At baseline, 31.4% of patients showed overt physical aggression, and after an average of 47 weeks of treatment with clozapine, this rate had fallen to 1.1%. The antiaggressive effects of clozapine were relatively specific and could not be explained by sedation or general antipsychotic effects. These effects were more pronounced than the effects on other symptoms and were also present in those patients who showed the highest pretreatment levels of hostility and aggression. Clozapine may also be of benefit in the treatment of schizophrenic patients with comorbid substance abuse. After 6 months of treatment with clozapine, substance abusers and nonabusers with schizophrenia or schizoaffective disorder showed similar improvements on measures of psychopathology and psychosocial functioning.

Atypical antipsychotics in the treatment of the persistently aggressive psychotic patient: methodological concerns.

Aggressive behavior of psychotic patients impacts all aspects of their clinical care. Better treatments to address this problem are needed, and atypical antipsychotics, such as clozapine, risperidone, and perhaps quetiapine, have shown promise. However, studying the psychopharmacology of aggression is difficult because of the many methodological problems that arise in the design of appropriate clinical trials. These include imprecise definitions of aggression, the difficulty of measuring outcome because of the relative rarity of aggressive events, bias in the selection of patients for study, inadequate and inappropriate control groups, and inattention to comorbidities and concomitant medications in analyzing results. Since the usual outcome measure is the aggressive event rate, a large sample size and lengthy baseline and trial periods are required when this rate is low. Furthermore, formidable practical and ethical obstacles interfere with the many sound techniques (e.g. randomization) used in typical designs of psychopharmacological clinical trials. Current research methods should be modified and new ones developed in order to progress in assessing the antiaggressive effects of treatments.