Schizophrenia and dopamine

Schizophrenia is a mental disorder causing a range of psychological symptoms such as delusions, hallucinations, disordered thinking, and abnormal motor behaviour, and which is considered by many as a neurodevelopmental disorder (Murray & Lewis, 1987; Weinberger, 2003). It affects 0.5–1% of the worldwide population, with a common onset in late adolescence to early adulthood (Perälä et al., 2007). The symptoms can be divided between positive symptoms, which are superimposed on the normal mental functions of the individual; negative symptoms, which are characterised by deficits in normal functions, such as alogia and avolition (Andreasen & Olsen, 1982); as well as cognitive deficits, such as poor executive functioning (Lesh et al., 2011). It is an heterogeneous disorder which makes it difficult to define (Tsuang et al., 1990).

Dysfunctions in the dopamine pathways have long been thought to be the main factor of symptoms in schizophrenia (Meltzer & Stahl, 1976). The so-called dopamine hypothesis posits that an increase in dopaminergic neurotransmission in the mesolimbic pathway causes atypical levels of dopamine in the striatum and the nucleus accumbens, causing the positive symptoms of schizophrenia, while dysfunctions in the mesocortical pathway may be responsible for the negative symptoms (Da Silva et al., 2008; Brisch et al., 2014).

Many positron emission tomography (PET) studies provide in vitro evidence supporting the dopamine hypothesis of schizophrenia by showing an association between dopamine hyperactivity and symptoms of schizophrenia in patients (Laruelle, 1998; Howes et al., 2012). To corroborate this hypothesis, it was additionally uncovered that antipsychotic drugs such as chlorpromazine work by binding to dopamine D2 receptors, acting as effective antagonists reducing neurotransmitter binding of dopamine in the mesolimbic pathway, thus reducing symptoms of schizophrenia (Ban, 2007).

But several discoveries are challenging the theory that elevated dopamine synthesis capacity is responsible for symptoms in all patients with schizophrenia. First, antipsychotics do not impact negative symptoms, which suggests the involvement of other neurotransmitters beside dopamine (Remington et al., 2016).

More importantly, not all patients with schizophrenia feature an increase in dopamine synthesis capacity. In fact, in contrast to dopaminergic antipsychotic treatment responders, treatment-resistant patients do not show any increase in dopamine in the striatum; instead, they show elevated levels of glutamate in the frontal cortex (Mouchlianitis, et al., 2015). This would suggest that treatment-resistant schizophrenic patients do not respond to antipsychotic drugs because their symptoms are not primarily caused by elevated dopamine synthesis capacity, and that there is at least two subtypes of schizophrenia (Howes & Kapur, 2014).

The existence of at least a second type of schizophrenia involving glutamate rather than dopamine synthesis is summarised by the N-methyl-D-aspartate (NMDA) Receptor Hypofunctioning Hypothesis of Schizophrenia, which posits that schizophrenia symptoms involve a dysfunction of NMDA receptors, and that drugs that modulate NMDA receptor currents could improve the symptoms of schizophrenia (Lindsley, 2006; Gao & Snyder, 2013).

But even this theory may be incomplete, for the dopaminergic, glutamatergic and GABAergic systems interact and regulate each other in complex ways. Some researchers are instead considering these interconnected systems as a whole, hypothesizing a final common pathway where multiple neuronal, receptors and neurotransmitter pathways converge to trigger the dopamine hyperactivity found in many schizophrenic subjects (Howes & Kapur, 2009; Schwartz et al., 2012).

What does this new theory mean for patients with schizophrenia? First, alternative drugs need to be developed for patients where elevated dopamine synthesis capacity is not present, and who do not respond to current dopaminergic antipsychotic treatments. Such glutaminergic drugs are currently being researched (Noetzel et al., 2012; Moreno et al., 2016). Second, more research needs to be conducted to identify the environmental and genetic risks accounting for the variability in both schizophrenia symptoms and the impacted neurotransmitter pathways, so appropriate treatments can be designed (Farrell et al., 2015). Some environmental factors for example include obstetrical complications, childhood traumas, socio-demographic factors, urbanicity, drug use, and infectious agents (Vilain et al., 2013). Potential genetic factors include the deletion of gene NRXN1 (Rujescu et al., 2008; Kirov et al., 2009) and a mutation of gene DISC1 (Hodgkinson et al., 2004; Kamiya et al., 2005).

Last, if these risks are identified and the neurodevelopmental nature of schizophrenia pathophysiology is confirmed, novel prevention strategies need to be researched to target the many functional and neuroanatomical changes taking place during early brain development, thus reducing the risk for developing schizophrenia (Rapoport et al., 2012).

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