Karen A. Nolan

Overt Aggression and Psychotic Symptoms in Patients with Schizophrenia Treated with Clozapine, Olanzapine, Risperidone, or Haloperidol

Abstract: The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.

Catecholamines and Aggression: The Role of COMT and MAO Polymorphisms

Abstract: Catecholaminergic systems are involved in the regulation of aggressive behavior; this regulation is implemented in interactions with other neurobiological mechanisms. Most of the available evidence indicates that norepinephrine and dopamine lower the threshold for an aggressive response to environmental stimuli. Two major enzymes are responsible for catecholamine catabolism in the brain: catechol‐O‐methyltransferase (COMT) and monoamine oxidase A (MAOA). The transcriptional activity of the genes coding for these enzymes is governed by common functional polymorphisms. If aggressive behavior is enhanced by catecholaminergic activity, then the lower activity of COMT and MAOA (resulting in a slower inactivation of catecholamines) should indirectly enhance aggression. This prediction has been supported by most (but not all) observations in rodents and humans. Male mice that have either the COMT or the MAOA gene knocked out show elevated aggression. The allele that codes for the lower enzymatic activity of COMT has been associated with elevated aggressive behavior in several samples of psychiatric patients. Similarly, the alleles that code for the lower activity of MAOA were associated with the development of aggressive behavior in maltreated male children in a large birth cohort study. Collectively, these results suggest that COMT and MAOA polymorphisms represent a basic neurobiological mechanism that contributes to the regulation of aggressive behavior.

Suicidal behavior in patients with schizophrenia is related to COMT polymorphism

&NA; 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.

Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study

We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O‐methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11‐item questionnaire that includes Aggression, Self‐Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self‐Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self‐directed aggressive behavior found in some schizophrenic patients.

Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study

Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers. Thirty subjects provided evaluable data on the MATRICS Consensus Cognitive Battery (MCCB), with the primary outcome measure, the MCCB Composite score. Active compared to sham tDCS subjects showed significant improvements after the fifth tDCS session in MCCB Composite score (p=0.008) and on the MCCB Working Memory (p=0.002) and Attention-Vigilance (p=0.027) domain scores, with large effect sizes. MCCB Composite and Working Memory domain scores remained significant at Benjamini-Hochberg corrected significance levels (α=0.05). There were no statistically significant effects on secondary outcome measures of psychiatric symptoms (PANSS scores), hallucinations, cigarette craving, or cigarettes smoked. The positive effects of tDCS on cognitive performance suggest a potential efficacious treatment for cognitive deficits in partially recovered chronic schizophrenia outpatients that should be further investigated.

Atypical antipsychotics, neurocognitive deficits, and aggression in schizophrenic patients

The purpose of this study was to compare the effects of olanzapine, clozapine, and haloperidol on neurocognitive function in schizophrenic patients who present with documented episodes of physical aggression and to determine whether change in cognitive function is related to aggression. One hundred physically aggressive schizophrenic inpatients were assigned to a randomized, double-blind, parallel-group, 12-week treatment, and received cognitive evaluations at baseline. There were 33, 34, and 33 subjects in the clozapine, olanzapine, and haloperidol groups, respectively. They were administered a battery of tests assessing psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. A general cognitive index was derived from the above battery. The overall score on the Modified Overt Aggression Scale was used to measure the number and severity of the aggressive events. Psychiatric symptoms and side effects were also assessed. The improvement in the general cognitive index differed significantly among the 3 treatment groups, with olanzapine being superior to both haloperidol and clozapine. Further analyses revealed significantly greater improvement with olanzapine in several cognitive domains. Furthermore, improvement in the general cognitive index was significantly associated with a decrease in aggression in the olanzapine group but not in the other 2 medication groups. In violent schizophrenic patients, olanzapine treatment is associated with better cognitive functioning relative to haloperidol and clozapine. This improvement in neurocognitive function is associated with a decrease in aggressive behavior. As clozapine markedly reduced aggression, there may be different pathways for the antiaggressive effect of olanzapine and that of clozapine.

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

&NA; 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 el al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Differential effect of catechol-O-methyltransferase Val 158 Met genotype on emotional recognition abilities in healthy men and women

The catechol-O-methyltransferase (COMT) Val158Met polymorphism modulates executive functions and working memory and recent neuroimaging studies implicate an association with emotional processing. We examined the relationship between the COMT Val158Met polymorphism and facial emotion recognition and differentiation in 100 healthy individuals. Compared to Met homozygosity, Val homozygosity was associated with better and faster recognition of negative facial expressions such as anger and sad. Our study provides evidence for a possible influence of the COMT polymorphism on emotion recognition abilities in healthy subjects. Additional research is needed to further define the neurocognitive phenotypes associated with COMT polymorphisms.

Self-report and laboratory measures of impulsivity in patients with schizophrenia or schizoaffective disorder and healthy controls.

This study examined self-reported impulsivity and aggression and performance on the stop-signal task in patients with schizophrenia or schizoaffective disorder and healthy volunteers. Compared to controls, patients had higher scores on interview and questionnaire measures of impulsivity and aggression and showed increased stop-signal reaction time and greater response variability. These findings are consistent with a specific impairment in response inhibition in schizophrenia.