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BACKGROUND: Exposure to developmental psychological stressors, adversity and trauma increases the risk of psychosis. Converging evidence indicates that developmental stress and trauma induce long-term changes in dopaminergic functioning which could give rise to a latent vulnerability to mental illness. I will therefore present a synthesis of the existent human and animal literature examining how developmental trauma and stress alters dopaminergic functioning in adulthood. In addition, I will present results of a study using positron emission tomography (PET) of dopamine synthesis capacity and the acute stress response in healthy adults exposed to developmental and adult psychosocial adversity. METHODS: We conducted a systematic review of the animal and human literature using a combination of three superordinate concepts including ‘childhood’, ‘trauma’ and ‘dopamine’ terms. The PET study used [18F]-DOPA in a case-control design (n=17 per group), with one group exposed to high levels of developmental and adult psychosocial adversity and another group exposed to low levels. Acute psychological stress was induced using the Montreal Stress Task. RESULTS: 140 studies were included in our review. Developmental stress and trauma results in long-term, complex changes in dopaminergic function across key cognitive domains including sensitization of the striatal dopaminergic response to stressors and frontal hypodopaminergia. Divergent alterations in dopaminergic function occurred depending on the timing of developmental exposure potentially representing critical periods. Developmental stress exposure potentiates aspects of dopaminergic processing including amplifying threat-related signaling in the ventral (limbic) striatum. This may occur alongside dopaminergic blunting in the amygdala resulting in deficits in fear extinction, impairing the ability to distinguish safe from unsafe environments. In our PET experiment, within people without psychosis long-term psychosocial adversity was associated with reduced baseline dopamine synthesis capacity and de-coupling between striatal dopamine and the acute stress response. Conclusions Developmental trauma exposure is likely to be inducing latent vulnerability to psychosis by producing lasting changes in reward, threat and executive processing. Further studies are needed to investigate the precise mechanisms underlying how trauma-induced changes in dopaminergic function induce vulnerability to psychosis and, in parallel, how dopaminergic processes may confer resilience.

This chapter presents case histories illustrating key aspects of the treatment of schizophrenia based on the authors’ clinical experience of patients that they have treated over the years, although identifying details have been changed. The art of clinical practice includes interpreting and applying evidence to help individual patients who often do not fit into the categories used in clinical trials. The cases show the application of evidence, and also its limitations, in real-world settings. This emphasizes the need for the evidence discussed throughout this book to be considered in the individual context of each patient. You will see variation in the approaches taken by the expert clinicians discussing their cases, reflecting how they interpret and apply evidence in a given clinical context. Each case is followed by a series of learning points and links to other chapters in the book where the issue is considered further.

Clear, accepted definitions of treatment resistance and response are needed so that clinical trials of treatments can be compared, and evidence can be meaningfully interpreted to inform clinical practice. In this chapter, we review the definitions of treatment response and resistance used in clinical trials, highlighting the variability in definitions used across studies, as well as a number of problems with the definitions used, including mixing treatment-intolerant patients with treatment-resistant patients and limited evaluation of the adequacy of treatment in many cases. The chapter then summarizes the work undertaken by the Treatment Response and Resistance in Psychosis working group to produce consensus guidelines and benchmarks to address these issues. Also reviewed are the principles underlying the concept of resistance developed by the working group. Finally, the chapter discusses the implications of these findings for clinical practice.

Schizophrenia and related disorders are common, affecting about 1 in 100 people, and typically begin in late adolescence and early adulthood, when people are in the prime of their lives. They are also major causes of disease burden globally and are amongst the top causes of disability in working-age adults in the world. Carers are significantly affected by the burden of these disorders, which are a leading cause of healthcare costs. Schizophrenia and related disorders are also major causes of premature mortality due to suicide and elevated rates of comorbid conditions, particularly cardiometabolic disorders. It is clear that the stakes are high, and this book aims to help the clinician give their patients the best odds of getting better.