Ikwunga Wonodi

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

Impairment of the kynurenine pathway (KP) of tryptophan metabolism has been suggested to play a role in the pathophysiology of schizophrenia and related cognitive deficits.^1-5 The KP generates 3 neuroactive metabolites with purported links to neuropsychiatric diseases.^6-8 These compounds—kynurenic acid (KYNA), 3-hydroxykynurenine, and quinolinic acid—are downstream products of the regulatory enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase, and kynurenine 3-monooxygenase (KMO) (Figure 1). The levels of KYNA, an endogenous antagonist of the glycine coagonist (glycine_B) site of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) and theα7 nicotinic acetylcholine receptor (α7nAChR),^6,9,10 are elevated in the prefrontal cortex and cerebrospinal fluid of schizophrenia patients.^1,11-13 This unique receptor affinity profile of KYNA is particularly interesting when viewed against accumulated evidence implicating NMDAR hypofunction in the pathophysiology of schizophrenia^14-19 andα7nAChR hypofunction in schizophrenia-related cognitive deficits.^20,21 In rats, endogenous KYNA controls extracellular levels of cortical acetylcholine, dopamine, and glutamate^22-24 and the firing rate and burst activity of midbrain dopaminergic neurons.²⁵ Remarkably, experimentally increased brain KYNA levels in rats induce deficits in visuospatial working memory, contextual learning, sensory gating, and prepulse inhibition of the acoustic startle reflex.^26-29 These neurocognitive deficits are of particular relevance to schizophrenia because they are highly frequent in schizophrenia individuals and their unaffected first-degree relatives and are considered endophenotypes.^30,31 Taken together, these findings suggest that cognitive deficits in schizophrenia could be causally related to elevated cortical KYNA concentrations.⁵

The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the α7 nicotinic acetylcholine receptor (α7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the α7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.

Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMTgene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized thatDAT110/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects ofDAT1genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), andDAT1gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia).DAT1genotype was not associated with schizophrenia.DAT110/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first‐degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study,DAT110/10 genotype was associated with significantly reducedDAT1mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulateDAT1gene function.

Recent years have witnessed increased antipsychotic treatment of children despite limited long‐term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic‐naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African–American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European–American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side‐effect profile of the atypical antipsychotic drugs in children may be much different than that in adults. © 2007 Movement Disorder Society