Split Mind: An Exploration of Structual and Biochemical Brain Abnormalities in Schizophrenia

Schizophrenia is a complex mental health disorder that can linger for a lifetime, often creating dependence on family and society. Originally dubbed dementia praecox (Latin, “premature mental deterioration”), schizophrenia is distinguished by an array of symptoms that are generally categorised into positive (e.g. hallucinations, delusions, abnormal motor behaviour), negative (e.g. alogia, anhedonia, decreased emotional expression), and cognitive (e.g. disorganised speech, ideas of reference, attentional deficits) (Patel et al., 2014). The complexity of the disease is highlighted by the fact that its possible to find multiple people with diagnosed schizophrenia with no common symptomatology (American Psychiatric Association, 2022). Diagnosis involves accounting for a spectrum of signs and symptoms typically associated with impaired social and cognitive functioning. Although the underlying mechanisms of schizophrenia remains largely unknown, multiple lines of research suggest that schizophrenia follows from the interplay of genetic and environmental factors (Kalat, 2019), beginning with pre- and peri-natal abnormalities that lead to neurological impairments that increase the likelihood of schizophrenia (Pearlson, 2000). Drawing on modern empirical research, this essay will argue that biochemical and structural abnormalities in the brain play a causal role in the aetiology and pathogenesis of schizophrenia.

Early social and psychological theories viewing familial and societal complications as leading causes of schizophrenia have given way to a growing body of evidence that views schizophrenia primarily as a brain disorder (Bland & Orn, 1981). According to the neurodevelopmental hypothesis (NDH), schizophrenia results from aberrations in brain development that may occur pre-, peri, and post-natally (Weinberger, 1995). Rather than inculpating family communication patterns or lack of social support as primary causal factors, the NDH asserts that schizophrenia results from static brain lesions acquired early in life that “remain silent until that structure of system matures” (Weinberger, 1987, p. 662). Multiple studies suggest that the brains of individuals diagnosed with schizophrenia showcase structural, physiological, and neurochemical abnormalities beginning before or in early childhood: most adult diagonisis demonstrate an array of neurologicaly-mediated issues since childhood, including attention deficit hyperactivity disorder (ADHD), memory impairments, and poor impulse control (Keshavan et al., 2005). In this same vein, damaging the dorsolateral prefrontal cortex (DLPFC) in rhesus monkeys, Goldman (1976) noticed that their behaviour slowly deteriorated as their brain developed: the effects of their brain damage grew as they aged. These results indicated that early structural damage may only become apparent as that region assumes functioning throughout the maturation process. However, the NDH lacks precision regarding the nature of the offending lesion: aberrations in early brain development underlie a wide range of adverse outcomes such as decreased intelligence quotient (IQ), epilepsy, and attention deficit disorder (ADD) (McGrath et al., 2003). Further explorations may benefit from identifying precise lesions that lead to schizophrenia. While clear-cut physiopathological mechanisms remain largely unknown, these data suggest that structural abnormalities in the brain play a causal role in schizophrenia.

The literature on schizophrenia has highlighted clear structural differences in the brains of normal individuals compared to those suffering from schizophrenia. While many obstetric complications (OCs) have been linked with schizophrenia, multiple studies have associated hypoxia-induced structural brain abnormalities with the later development of schizophrenia (Cannon et al., 2002). Hypoxia may be defined as a low levels of oxygen in body tissues (Diaz, 2001). Because lack of oxygen in the perinatal period is common across OCs in both human and animal studies, it may be the case that hypoxia is central to abnormal fetal growth (Robinson & Bergen, 2021), thus playing a causal role in schizophrenia. Similarly, Dalman et al (2001) found that perinatal hypoxia is associated with over four-time the odds of developing schizophrenia even when controlling for other biological and social factors such as maternal health status and socioeconomic status, while Cannon et al. (2002) showed that individuals with over three hypoxia-related OCs were over five-times more likely to develop schizophrenia compared to those with no hypoxia-related OCs.

Multiple magnetic resonance imaging (MRI) studies have confirmed lateral ventricular enlargement in patients with schizophrenia: a meta-analysis (n = > 18,000) carried out by Haijma et al. (2013) demonstrated a 25% increase in ventricular size compared to non-schizophrenic individuals, alongside a 2% reduction in brain volume. Dendritic spines of neurons in the prefrontal cortex (PFC) of individuals with schizophrenia have reduced density compared with control participants (Glantz & Lewis, 2000). In this same vein, Palaniyappan and Balain (2012) found that reduced volume in the insula, superior temporal gyrus, and cingulate are associated with individuals at high risk of developing schizophrenia. Consistent across the literature is the association between enlargement of the third and lateral ventricles and slight reductions in total brain volume and grey matter volume in patients with schizophrenia (Padmanabhan & Keshavan, 2014). While these results point to structural abnormalities playing a role in schizophrenia, the relationship between abnormal brain development and schizophrenia is not fully understood. For example, research has shown that first-generation neuroleptic (FGN) drugs may increase the size of the caudate over time, while long-term FGN use has been associated with grey matter loss over time (Keshavan et al., 1994). Further research could usefully explore the nature of the relationship between biochemical and structural brain alterations and schizophrenia. Overall, the above evidence seems to support the notion that biochemical and structural abnormalities in the brain play a role in producing schizophrenia.

Previous explorations into the impact of dopamine dysfunction on schizophrenia have been inconsistent and contradictory. The original dopamine hypothesis put forward that overactivity of dopamine transmission resulted in the symptomology of schizophrenia, whereas the revised dopamine hypothesis suggests that a combination of hyperactivity of mesolimbic dopamine systems and hypoactivity of the PFC leads to schizophrenia (Brisch et al, 2014). Dopamine receptors can be roughly divided into the D1 and D2 subtypes, the former being associated with memory, attention, impulse control, regulation of renal function, and locomotion, and the latter, with locomotion, attention, sleep, memory, learning (Bhatia et al., 2022; Verharen et al., 2019). Positive symptoms are hypothesised to result from augmented D2 receptor activity from the increased subcortical release of dopamine and perturbations of the mesolimbic pathway through the nucleus accumbens, while negative symptoms are thought to result from diminished D1 receptor activity through the caudate nucleus (Shen et al., 2012; O’Donnell & Grace, 1998). Neuroleptic agents tend to reduce psychotic systems by blocking D2 receptors: research has confirmed that antipsychotic agents that most effectively alleviate symptoms of schizophrenia are those which are most effective at blocking D2 receptors (Howes & Kapur, 2014). While the above evidence suggests that biochemical abnormalities are associated with schizophrenia, the relationship between dopaminergic dysfunction and schizophrenia remains unclear.

Recent research implies that dopamine dysfunction is a secondary effect of other deficits in the aetiology schizophrenia. Reviewing the dopamine literature, Grace (2016) put forward that dopamine dysfunction itself is not the primary cause of schizophrenia, but rather a secondary effect of other abnormalities such as structural deficits in the brain that converge to increase the likelihood of schizophrenia. These results suggest that structural abnormalities in the brain induce pathological biochemical functioning, which may coalece to induce symptoms of schizophrenia. The lack of clarity in the relationship between dopamine and schizophrenia may be that a majority of the literature was informed by indirect measurements, including dopamine levels and receptor density in postmortem brain tissues (Mackay et al., 1982). However, the introduction of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging enabled the investigation of in vivo cerebral dopamine neurotransmission free of these limitations (Howes, 2012). Leading on from this, Laruelle (1998) reviewed studies using SPECT and PET imaging to measure dopaminergic function in drug-naive or drug-free patients with schizophrenia with healthy controls. Aligning with previous findings, results showed that schizophrenic patients possess a significant elevation of D2 receptor density parameters. In general, therefore, the evidence presented suggests that structural and biochemical abnormalities may work synergistically to bring about schizophrenia.

Data from several studies have highlighted links between glutamate and schizophrenia. While dopamine is limited to specific brain regions, glutamate is present throughout the entire nervous system (Moghaddam & Javitt, 2012). The relevance of glutamate in the pathophysiology of schizophrenia was discovered through research on synthetic N-methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and ketamine (Padmanabhan & Keshavan, 2014): these antagonists induce schizophrenia-like symptoms by binding specifically to the NMDA receptor (Javitt et al., 1996). From this data, researchers concluded that the pathophysiology of schizophrenia involved the hypo-activation of NMDA receptors and dysfunctional glutamate neurotransmission (Moghaddam & Javitt, 2012). This is supported by work from Coyle et al. (2003), who found that administration of low doses of NMDA receptor antagonists can induce negative symptoms, cognitive impairments and physiologic disturbances characteristic of schizophrenia. The evidence presented suggests that diminished glutamatergic activity results in symptoms of schizophrenia, indicating that abnormal biochemistry plays a role in schizophrenia. On the other hand, research by Schobel et al. (2013) proposes that an excess—rather than a lack —of glutamine may be the driving force behind the disease process. The excess glutamine hypothesis is supported by findings that suggest stress increases glutamate synthesis in the nervous system and that stressful experience often precede first-episode psychosis (Perry et al., 2016). While the precise relationship between glutamate and schizophrenia remains ambiguous, these results provide support for the hypothesis that biochemical abnormalities in the brain play a causal role in producing schizophrenia.

The literature has consistently demonstrated a relationship between cannabis, developmental pathology, and schizophrenia. Multiple studies have linked the onset of schizophrenia to an interaction between adolescent cannabis use and the Catechol-O-Methyl-Transferase (COMT) gene, which comes in two forms: Val and Met. Some studies have shown that cannabis users with one or two copies of the Val gene have a higher risk of developing symptoms of schizophrenia, while users with two copies of the Met variant were unaffected (Caspi et al., 2005). These findings were later corroborated by Estrada et al. (2011), who extended these findings by arguing that the COMT genotype modulates the relationship between cannabis use and brain maturation at the onset of psychotic disorders: the earlier cannabis was used, the earlier the onset of the disease. This suggests that cannabis interferes with the brain development and maturity of the user, perhaps through a genetic sensitivity to the dopamine-modulating effects of cannabis. That said, cannabis alone may not be sufficient to trigger psychosis: cannabis remains the most popular recreational drug in the world, yet the number of cannabis-induced psychotic episodes remains far below the number of worldwide users (WHO, 2022). It may be the case that cannabis interacts with abnormal brain biochemical and structural profiles to induce schizophrenic-like symptoms (Robinson & Bergen, 2019). As cannabis is the most widely used recreational drug in the world, further research exploring the precise mechanisms through which cannabis brings about psychosis may prove beneficial if our goal is overall harm reduction. Overall, the data presented in this section lend further support to the view that biochemical and structural abnormalities play a causal role in producing schizophrenia.

Schizophrenia is a serious mental health disorder in which sufferers interpret reality abnormally. The purpose of this essay was to explore the relationship between biochemical and structural brain abnormalities and schizophrenia. While the neurobiological basis of schizophrenia was postulated over a century ago, little evidence of a relationship between biochemical and structural brain abnormalities emerged in the intervening years (Padmanabhan & Keshavan, 2014). However, modern research has established beyond doubt that biochemical and structural brain abnormalities play a role in the aetiology and pathogenesis of schizophrenia. While our understanding of schizophrenia has come a long way, schizophrenia remains largely untreatable. Considering the impact of schizophrenia on individuals, their families, and wider society, further research with the goal of identifying, understanding, and treating the underlying mechanisms of the disease would be of service to the greater good.

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