Commentary

Neural Circuitry Models of Schizophrenia: Is it Dopamine, GABA, Glutamate, or Something Else?

Treatment-resistance in schizophrenia is 30–40%. Its neurobiology remains unclear; to explore it, we conducted a combined spectrometry/tractography/cognitive battery and psychopathological rating study on patients with treatment-resistant schizophrenia (TRS), dividing the sample into early-onset (N = 21) and adult-onset TRS (N = 20). Previous studies did not differentiate between early- (onset 13–18 years) and adult-onset (>18 years at formal diagnosis of schizophrenia) TRS.

We evaluated cross-sectionally 41 TRS patients (26 male and 15 female) and 20 matched healthy controls (HCs) with psychopathological and cognitive testing prior to participating in brain imaging scanning using magnetic resonance spectroscopy and diffusion tensor imaging to determine the relationship between their symptoms and their glutamate levels and white matter integrity.

TRS patients scored lower than HCs on all cognitive domains; early-onset patients performed better than adult-onset patients only on the Symbol Coding domain. TRS correlated with symptom severity, especially negative symptoms. Glutamate levels and glutamate/creatine were increased in anterior cingulate cortex. Diffusion tensor imaging showed low fractional anisotropy in TRS patients in specific white matter tracts compared to HCs (bilateral anterior thalamic radiation, cortico-spinal tract, forceps minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and right uncinate fasciculus).

We identified specific magnetic resonance spectroscopy and diffusion tensor imaging alterations in TRS patients. Adult-onset TRS differed little from early-onset TRS on most measures; this points to alterations being present since the outset of schizophrenia and may constitute a biological signature of treatment-resistance.

Heme plays a role in major cellular processes such as signal transduction, protein synthesis, and complex assembly and regulation of transcription and translation. As such, it is essential for brain metabolism, oxygen sensing, and neuronal survival. Its synthesis is composed of eight distinct steps; the first and last three steps take place in the mitochondria. Accumulating evidence point at mitochondrial dysfunction and altered heme metabolism in neuropsychiatric disorders. Here, we will review the growing number of experimental data demonstrating deficits in heme, mitochondria, and specifically the first complex (Co-I) of the electron transport chain in three neuropsychiatric disorders—Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SZ). Furthermore, we will provide evidence for an association between mitochondrial Co-I dysfunction and heme metabolism and suggest their potential to become additional therapeutic targets that will improve the efficiency of the current treatments.

Heme plays a role in major cellular processes such as signal transduction, protein synthesis, and complex assembly and regulation of transcription and translation. As such, it is essential for brain metabolism, oxygen sensing, and neuronal survival. Its synthesis is composed of eight distinct steps; the first and last three steps take place in the mitochondria. Accumulating evidence point at mitochondrial dysfunction and altered heme metabolism in neuropsychiatric disorders. Here, we will review the growing number of experimental data demonstrating deficits in heme, mitochondria, and specifically the first complex (Co-I) of the electron transport chain in three neuropsychiatric disorders—Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SZ). Furthermore, we will provide evidence for an association between mitochondrial Co-I dysfunction and heme metabolism and suggest their potential to become additional therapeutic targets that will improve the efficiency of the current treatments.

The present study investigates the neural substrates underlying cognitive processing in schizophrenia (Sz) patients. To this end, an auditory 3-stimulus oddball paradigm was used to identify P3a and P3b components, elicited by rare-distractor and rare-target tones, respectively. Event-related potentials (ERP) were recorded from 31 Sz patients and 38 healthy controls. The P3a and P3b brain-source generators were identified by time-averaging of low-resolution brain electromagnetic tomography (LORETA) current density images. In contrast with the commonly used fixed window of interest (WOI), we proposed to apply an adaptive WOI, which takes into account subjects' P300 latency variability. Our results showed different P3a and P3b source activation patterns in both groups. P3b sources included frontal, parietal and limbic lobes, whereas P3a response generators were localized over bilateral frontal and superior temporal regions. These areas have been related to the discrimination of auditory stimulus and to the inhibition (P3a) or the initiation (P3b) of motor response in a cognitive task. In addition, differences in source localization between Sz and control groups were observed. Sz patients showed lower P3b source activity in bilateral frontal structures and the cingulate. P3a generators were less widespread for Sz patients than for controls in right superior, medial and middle frontal gyrus. Our findings suggest that target and distractor processing involves distinct attentional subsystems, both being altered in Sz. Hence, the study of neuroelectric brain information can provide further insights to understand cognitive processes and underlying mechanisms in Sz.

Schizophrenia is a devastating mental illness that afflicts nearly 1% of the world’s population. Currently available antipsychotics treat positive symptoms, but are largely ineffective at addressing negative symptoms and cognitive dysfunction. Thus, improved pharmacotherapies that treat all aspects of the disease remain a critical unmet need. There is mounting evidence that links NMDA receptor hypofunction and the expression of schizophrenia, and numerous drug discovery programs have developed agents that directly or indirectly potentiate NMDA receptor-mediated neurotransmission. Several compounds have emerged that show promise for treating all symptom sub-domains in both preclinical models and clinical studies, and we will review recent developments in many of these areas.

This paper is aimed at criminologists and criminal justicians seeking to understand their role in educating law enforcement and correctional personnel who must deal with the mentally ill. It is motivated by William Johnson's (2011) recent call for rethinking the interface between mental illness, criminal justice, and academia, and his call for advocacy. We concur with his concerns, and insist that this rethinking must necessarily include grounding in the etiology of mental illness (specifically, with schizophrenia) as it is currently understood by researchers in the area. Advocacy must go hand in hand with a thorough knowledge of the condition of the people for whom we are advocating. We first examine major etiological models of schizophrenia, emphasizing the neurodevelopmental model that incorporates genetics, neurological functioning, and immunological factors guided by the assumption that the typical criminologist/criminal justician has minimal acquaintance with such material. We then address the link between schizophrenia and criminal behavior, and conclude with a discussion of the implications for criminology and criminal justice.