Schizophrenia is a chronic neuropsychiatric disorder that can begin in late adolescence and early adulthood with an array of severe symptoms, including hallucinations and delusions. When left untreated, these symptoms can disrupt an individual’s cognitive, social, and emotional functions and make it difficult for them to complete everyday tasks. Although the advent of modern neuroimaging techniques has helped scientists make great strides in understanding schizophrenia, researchers have long debated whether schizophrenia is caused by neurodevelopmental processes, specifically neurotransmitter activity and interactions between developmental genes, or by excessive neural pruning, which is loss of matter in crucial areas of the brain.  [1]  In recent years, it has become widely accepted that both processes play a role in the progression of schizophrenia. This view is reflected in the current model, diathesis-stress, which acknowledges the influence of both neurodevelopmental and neural pruning theories. The diathesis-stress model’s more holistic understanding of schizophrenia will inevitably change how researchers approach the treatment of this disorder.

The neurodevelopmental theory suggests that differences in the brain’s processes and structure during adolescent development culminate in the onset of schizophrenia in genetically vulnerable individuals. It is well known that abnormal dopamine activity in the brain is characteristic of schizophrenic patients.  [2]  The neurodevelopmental theory proposes that abnormal dopamine behavior can be genetically conferred. Brain development and neural connectivity are regulated by certain genes, so irregular expression of those genes can negatively affect neurodevelopment and increase the risk of developing the disorder.  [3, 4, 5]  One study showed that certain genetic mutations lead to abnormal neural networks that contribute to schizophrenia.  [6]  At the same time, hormonal changes during adolescence affect both the gene expression involved in neurodevelopment and the various neurotransmitter pathways involved in neural circuits.  [7]  Specifically, the hormone receptors on the surface and in the interior of neurons have short-term and long-term effects, respectively. The short-term “nongenomic” effects of the hormone-surface receptor interactions change neuronal excitability and neurotransmitter release. The hormone-receptor interactions on the interior of the cell have “genomic” effects because they can alter long-term gene exneuropression in the neuron.  [7]  The many processes contributing to brain development during adolescence, such as neurotransmitter activity and gene expression, can impact how an individual functions.

Neural pruning theories specifically focus on the impact of grey matter reduction on the symptoms of schizophrenia. Although some reduction is characteristic of adolescent development, it is more extreme in schizophrenic patients. Adolescent years are key for reducing grey matter volume and pruning neural connections that are no longer useful. In a normal adolescent brain, the rate of grey matter loss is around one to two percent a year. In comparison, the rate of loss is around three to four percent a year in individuals with schizophrenia.  [1]  Many MRI studies of schizophrenia show that this reduced grey matter volume occurs in critical regions of the brain involved in episodic memory, auditory processing, short-term memory, and decision-making.  [8]  The reduction in these key areas is thought to be a major contributing factor to the hallucinations, delusions, and behavioral symptoms of schizophrenia.  [2]  Because this process is influenced by gene expression, it can also be affected by hormonal changes during adolescence, similar to the effect on neurotransmitter pathways and neural circuits.

The diathesis-stress model for schizophrenia acknowledges the influence of both neurodevelopmental and neural pruning theories, identifying a hormone feedback loop that could be linking the two underlying processes. Elaine Walker and her colleagues at Emory University developed this model through extensive research on the development of schizophrenia-prone adolescent brains.  [1]  Adolescence is characterized by an increase in adrenal hormones, which are involved in the biological stress response. These changes in hormone levels in the brain can adversely affect brain function and development through abnormal neurotransmitter release.  [2]  Akin to the neurodevelopmental perspective, Walker was particularly interested in how increased activity in dopamine pathways following the onset of puberty affected the developing brain.  [1]  The contributions of the neural pruning theory, however, could not be ignored, so she hypothesized that the hyperactivity of dopamine in certain brain regions combined with the decrease in grey matter during adolescence could contribute to the progression of schizophrenia.

In order to complete the model, Walker and her colleague Kevin Tessner proposed a positive feedback loop mechanism between hormones, neurotransmitters, and their ultimate effect on grey matter. Excess stress exposure leads to hyperactivity of critical structures of the endocrine system: the hypothalamus, the pituitary gland, and the adrenal gland; causing an increase in cortisol secretion.  [1]  The increase in cortisol triggers dopamine activity and activates genes that code for synaptic pruning at a higher rate than normal, which contributes to elevated grey matter decline and volume reduction in the hippocampus. These changes result in increased impairment in cognitive, social, and emotional functioning, in turn leading to increased stress.  [1]  In response, the cycle starts again and exacerbates the process, ultimately resulting in the first psychotic episode. Although this mechanism described the interaction of neurodevelopmental and neural pruning processes, Walker still needed to describe a connection between the feedback loop and genetic vulnerability.

Walker linked genetic vulnerability to the proposed feedback loop with the diathesis-stress model. Essentially, the diathesis-stress model argues that genetic vulnerability will only lead to behavioral symptoms once psychological stressors exceed the individual’s ability to cope.  [1]  Walker asserted that hereditary traits lead to vulnerability while stressors influence adolescent development through the hormone feedback loop.  [7]  In this way, genetic vulnerability only leads to schizophrenia once enough stressors trigger the positive feedback loop. This holistic model successfully incorporates observations from both neurodevelopmental and neural pruning perspectives and connects these observations with genetic factors.

The diathesis-stress model and the feedback loop show that schizophrenia is the product of an interaction between multiple neurodegenerative and neurodevelopmental processes. This model will undoubtedly refocus schizophrenia treatment. Currently, schizophrenia treatments are primarily focused on antipsychotic drugs and various psychotherapies, including family education, individual therapy, and supported education and employment.  [1]  Antipsychotics are usually successful at preventing and suppressing hallucinations and delusions; however, if patients stop using the drugs, the symptoms can return with increased intensity because the current medications do not treat the root causes of schizophrenia.  [9]  Additionally, medication is just one aspect of schizophrenia treatment, but patients might not have access to other options. If patients do have access to psychotherapy treatment, it can improve their day-to-day functioning by giving them psychological strategies to mediate the effects of the disorder on their social interactions and daily lives.  [10]  Although these kinds of treatments can dramatically improve a patient’s condition, the danger of a relapse is always present because psychotherapy cannot cure schizophrenia. Walker’s model gives new insight into how genetic vulnerabilities influence certain neural mechanisms that give rise to psychotic episodes and symptoms, which will help researchers explore new ways of approaching treatment. On the medication side, researchers might explore how medicine can regulate different parts of the feedback loop. On the psychotherapy side, researchers might examine how preventative intervention during adolescent development could change the progression of the disorder by understanding the gene-environment interactions that translate genetic vulnerabilities into schizophrenia.  [10]  Moving forward, the diathesis-stress model will allow researchers to more directly address the root causes of schizophrenia in medication-based treatment and will encourage psychological techniques that play a role in preventative measures as well as regulative ones.

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