Depression and neuroprogression: Sirtuins and mitochondria as crucial hubs

Neuroprogressive processes in major depressive disorder (MDD) can occur in association with recurrent episodes. The primary biological underpinnings are mediated by increases in the levels of immune-inflammation, tryptophan catabolites, mitochondrial dysfunction, and oxidative and nitrosative stress. Such biochemical alterations may be driven by changes in many peripheral and central sites, including in the gut, as well as by early developmental priming, such as prenatal stressors and breastfeeding consequences. As such, the conceptualization of MDD is shifted from simple psychological and central biochemical models to one that includes whole body processes over a developmental timescale. This provides a model that better integrates wider bodies of data relevant to the aetiology and course of MDD, and which therefore underpins the neuroprogressive processes that can occur over the course of MDD. This also significantly challenges current MDD (and wider psychiatric) classification by shifting classification to one based on biological processes rather than one based on subjective phenomenology.

Lifestyle and neuroprogression: Diet, sleep, and exercise

Diet, sleep, and exercise are lifestyle factors important for the prevention and treatment of psychiatric disorders, including major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. These lifestyle factors can contribute to dysregulation in important physiological mechanisms associated with psychiatric disorders and influence neuroprogression. We review research highlighting the important role of these lifestyle factors for different psychiatric conditions, and examine the potential mechanisms behind their therapeutic effects, with a particular emphasis on how they may each influence neuroprogression.

Substance abuse and neuroprogression

There is a growing body of evidence suggesting that neuroprogression occurs in addiction in the same way as in other psychiatric disorders. Biological markers of neuroprogression will be reviewed in the light of the staging model of addiction proposed by Volkow and Koob (intoxication, withdrawal and negative affect, and preoccupation and anticipation) and of allostatic load theory. Chronic exposure to drugs leads to allostatic load or overload through these stages. Neuroadaptation in this process disrupts brain morphology and function. Evidence regarding neuroprogression in drug addiction will focus on neuroimaging findings as well as neurotrophins, inflammatory markers, oxidative stress, and accelerated ageing.

Neuroprogression in children and adolescents with bipolar disorder

The concept of neuroprogression in children and adolescents with bipolar disorder is still under construction and remains controversial. It encompasses the notion of a temporal progression of illness with regard to its neurobiology, phenomenology, treatment response, and associated functional impairment. In this chapter, we review current evidence surrounding this concept. There is a definite clinical progression from an asymptomatic risk status, the appearance of the prodromal affective symptoms, and, finally, to the onset of illness. Some, but not all, neuroimaging, neuropsychological, and pharmacological studies support the notion of functional and structural brain differences between high-risk individuals and control subjects. Furthermore, current evidence of neuroprogression after illness onset is frail. Most relevant studies are cross-sectional, with few longitudinal exceptions. We will discuss neuroprogression, its use in the context of clinical staging, and other controversial areas regarding this concept in youth with bipolar disorder.

The pernicious procession of somatoprogression

Psychiatric disorders predispose individuals to physical illness and premature mortality. ‘Somatoprogression’ refers to the accumulation of medical comorbidities that occurs parallel to the chronological deterioration of the mental illness (known as neuroprogression). Psychiatric illness engenders increased medical burden via lifestyle factors, adverse pharmacological effects, differential healthcare access, and illness-related perturbations in psychobiological systems. Because medical comorbidities simultaneously exacerbate the course of mental disorders, the relationship between psychiatric and somatic illness is bidirectional. Moreover, the multitude of shared risk factors points to common pathoaetiological processes, which emerge as both medical and psychiatric phenomena. The allostatic load model provides a framework to understand the interrelationship of the processes underlying neuroprogression and somatoprogression. In bipolar disorder, somatoprogression manifests as increased risk of endocrine/metabolic, inflammatory, and cardiovascular disease, subserved by chronic inflammation, oxidative stress, and reduced neurotrophic support. Importantly, converging evidence suggests a synergy of affective progression and somatoprogression in the development of cognitive impairment.

Neuroprogression in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) has a lifetime prevalence of 10–12% in women and 5–6% in men. Patients with PTSD are at greater risk for obesity, type 2 diabetes mellitus, atherosclerosis, and myocardial infarction. In addition, a subset of these patients develops cognitive impairments unattributable to age or disease comorbidity alone, with hippocampal and prefrontal cortex atrophy. This chapter aims to review the evidence for neuroprogression in PTSD. This concept has been proposed as the pathological rewiring of the brain that takes place in parallel with the clinical and neurocognitive deterioration in the course of some psychiatric disorders. We will also review the biological pathways underlying neuroprogression in PTSD, including changes in inflammatory cytokines, corticosteroids, neurotrophins, and oxidative stress markers.

The role of immuno-inflammatory abnormalities in neuroprogression

Immuno-inflammatory dysfunction has become a well-consolidated contributor to mental illness pathophysiology. A consistent body of evidence supports the involvement of the immune system in symptomatic expression during acute episodes of severe mental illnesses, but also suggests that this system is involved in longitudinal trajectories of disease. Several explanations have been proposed as possible causes of immune-inflammatory abnormalities in severe mental illnesses, including genetic factors, environmental factors, and complex phenomena such as the premature ageing of the immune system (immunosenescence). Considering the heterogeneity in illness trajectories and the remarkable interindividual variation of immune parameters in individuals with mental illness, it is possible that, for each individual, a unique set of factors operates in a complex interaction of causative and moderator agents. A personalized approach to the role of inflammation in neuroprogression is probably the future for prevention and development of disease-modifying interventions.

Mitochondrial function and inflammation pathways in the neuroprogression of mental disorders

Stress, mitochondrial dysfunction, and inflammation are key pathophysiological processes contributing to neuroprogression in mental illness. These factors independently and collectively impact critical cellular mechanisms essential for healthy brain development and function. As these damaging processes continue, cellular debris (damaged DNA and proteins) accumulates, and neuronal integrity is impaired. In addition to this, the myelin sheath that encapsulates neurones to enable smooth and efficient communication throughout the brain is impaired. This chapter outlines how these factors are impacted by stress, inflammation, and mitochondrial function and how they work independently, and together, to increase risk for the development of mental illness, as well as to promote neuroprogression of the illness over time. We discuss how targeting these pathophysiological processes through interdependent factors such as the NLRP3 inflammasome, which sits at the intersection of these mechanistic pathways, may unlock opportunities to limit neuroprogression in the future.

Neuroprogression and accelerated ageing in severe psychiatric disorders

A convergent body of evidence suggests an overlap between neural, molecular, and functional findings in patients with severe mental illnesses and normative ageing. Patients in late stages of mood disorders and psychosis present brain changes and cognitive decline consistent with a pattern of accelerated ageing. In addition, replicated but heterogeneous findings support the notion that individuals with major depressive disorder, bipolar disorder, and schizophrenia have shorter telomeres compared to age-matched healthy controls. The recognition that severe mental illnesses are associated with premature or accelerated ageing offers new avenues of investigation for really novel therapeutic approaches. The hope is that these interventions will not only treat symptoms but be able to modify the course of these psychiatric conditions.

A short introductory note about neuroprogression in psychiatry

This chapter shows how the field of neuroprogression and staging has evident conceptual and historical connections with past clinical and research efforts made in Europe during the first half of the nineteenth century. ‘Psychiatrie’ was a new branch of medicine trying to find and define disorders within the psychic, symptomatic, and behavioural realms. Disorders, and boundaries between them, were still largely unknown, as well as the course of clinical presentation. As early as 1850, theory and research pointed to some unifying perspectives with characteristic ‘evolving deterioration in transformation’. Some classical descriptions of ‘stages’ and ‘phases’ of disease bear clear resemblance to current staging models. ‘Phrenalgie’ and ‘Seelenschmerz’, for example, correspond essentially to the current definitions of ‘initial vulnerability’ or ‘increased risk’. Relating severity of presentation and intensity of recurrence to bad prognosis became clear and opened empirical ways to understand pathophysiology, reframed nowadays under the ideas of neuroprogression and staging.