This book has focused upon the prevalent and important interface of depression and medical illness. The clinical, personal, familial, societal, and financial impacts of this interaction are tremendous. The state of our knowledge and experience concerning this nexus has been detailed, across the spectrum of medical conditions, populations, and settings. Much of this understanding has been facilitated by recent advances in scientific methods, and much has resulted from of careful clinical observation. These converging approaches have been discussed, and resultant principles have been explicated. With this substantial foundation, what are we building toward?

In essence, the goal is a mechanistic understanding that can provide diagnostic and therapeutic tools to improve outcomes, and guide clinical decision making. To accomplish this goal, one must utilize evolving approaches to chart the biopsychosocial intersection of depression and medical illness. This requires a characterization of the heterogeneity of depressive illness, of the range of medical illnesses, and of the types of mechanistic interrelationships among them. It also requires an elucidation of the final common brain pathways mediating depressive symptoms, as well as the pathophysiologic pathways and the etiological factors and interactions affecting those brain pathways in the context of medical illness.

Depression, even Major Depression, is not a unitary phenomenon. It is currently defined descriptively, and a patient can meet clinical criteria with different symptom constellations. Furthermore, there can be considerable overlap with other psychiatric syndromes, including anxiety disorders. With advances in translational research, it will be possible to stratify patients along a dimensional spectrum, within and across DSM categories, through deep phenotyping, multi-modal biomarkers and informatics.¹ This will result in a mechanism-based taxonomy of depressive/mood disorders, with implications for treatment targets that modulate the relevant biological substrate, through pharmacologic, cognitive-behavioral or brain stimulation approaches.² For example, there is increasing evidence for an anhedonic syndromic subtype with prominent lack of interest or pleasure in activities, associated with ventral striatum/nucleus accumbens, dopaminergic reward/motivation circuit dysfunction (Fig. 24-1).^3,4

Patterns of distributed brain activity/connectivity may also be able to distinguish patients from healthy subjects, providing a possible foundation for future diagnostic approaches (Fig. 24-2).⁵

In addition to systems-level neuroimaging, with both functional and structural elements, other biomarkers can provide cellular and molecular information of relevance. Metabolomics, proteomics, lipidomics, epigenomics, and genomics provide a range of powerful techniques that are starting to provide relevant data.⁶ Ultimately, a particular patient may be described in a personalized medicine approach by a profile of abnormalities in these domains, specifying associated therapeutic agents, as happens increasingly with cancer patients.⁷

Among the many medical illnesses affecting different organ systems, common underlying biological mechanisms are being identified. These represent pathophysiologies or disruption in signaling pathways that regulate function at the systems or cellular level. Vascular, endocrine, infectious, degenerative, toxic, metabolic, and other etiologies may be implicated.⁸ Processes such as inflammation, oxidative stress, and apoptosis can play a critical mediating role, in the context of genetic, developmental, and aging factors.^9,10

TYPES OF MECHANISTIC INTERACTIONS AMONG PSYCHIATRIC AND MEDICAL ILLNESSES

Much of this book expounds the importance of understanding the variance and commonalities within and among the psychiatric presentations, as well as the variance and commonalities within and among the medical presentations—and their interactions. In a patient with depression and diabetes, for example, the relationship between these two disease elements may be multidetermined, biologically and psychologically/behaviorally. One condition can play a causal or contributing role in the other (in either direction), they may coincidentally co-occur and interact, and/or they may both result from a common underlying diathesis.^11,12 Stress, inflammation, insulin resistance, eating behavior, and medical adherence may all be involved.¹¹ There are also intriguing observations, such as demonstration that SSRI medication can improve medical outcome in some cases even in the absence of an improvement in depression.^13,14 Recognizing, addressing, and studying these complex interrelationships can improve clinical care, and can inform impactful translational research strategies. This can also help to extend and transcend the concept of comorbidity.

FINAL COMMON BRAIN PATHWAYS MEDIATING DEPRESSIVE SYMPTOMATOLOGY

Ultimately, these effects are mediated via final common pathways of brain dysfunction. The brain regions and circuits that underlie processes such as emotion, motivation, salience, behavior, executive function, and vegetative function are thus critical to distinguish. Excess or diminished activity, abnormal connectivity, aberrant modulation, feedforward/feedback or inhibition, or altered thresholds can produce distinct neuropsychiatric symptoms.^15,16 This is not unlike the localization of neurologic syndromes, due to the hard-wiring of many structure–function relationships in the brain, from those mediating the most basic to the most human behaviors (the biological bases of which are being increasingly understood). Indeed, neuroimaging is identifying key dorsolateral prefrontal, subgenual anterior cingulate, amygdalar, hippocampal, insular, and ventral striatal substrates of depression and its subtypes.^5,17 Neurological lesions or processes that involve such regions and associated circuits can produce depressive phenomenology.¹⁸

RELEVANT NEUROPHYSIOLOGICAL PROCESSES

Critical neurophysiological processes on the local neuronal circuit and cellular level are relevant as well. Neurogenesis in the hippocampus, for instance, is enhanced in all effective treatments of depression, with the involvement of trophic factors, such as brain-derived neurotrophic factor (BDNF).¹⁹ Synaptic plasticity and dendritic arborization (communication and connections among neurons) are implicated.¹⁹ Interneurons and astrocytes have also been implicated due to their important roles regulating the neuronal, neurochemical, and glial micro-environment.^20,21

RELEVANT PATHOPHYSIOLOGICAL PROCESSES

A number of processes have a beneficial or deleterious effect on such local neurophysiology. These processes have been implicated in depression or its treatment, and are of relevance in the medical setting. Excitotoxicity may contribute to stress-mediated hippocampal damage,²² along with cortisol;²³ and excitatory neurotransmission via glutamatergic NMDA receptor subtypes is a current target for blockade with rapidly acting antidepressants.²⁰ GABA inhibition-enhancing benzodiazepines can interfere with hippocampal neurogenesis.²⁴ SSRIs and estrogen may enhance neurogenesis.^25,26 Cytokines play roles in neural signaling and plasticity as well as in inflammation, and proinflammatory cytokines (such as TNF-alpha and IL-6) have been associated with depression (and decrease with treatment, with therapeutic implications being explored).²⁷ Oxidative stress may also disrupt neurogenesis,²⁸ and cellular aging (reflected by telemorase activity) has been associated with hippocampal volume in major depression.²⁹ Abnormal metabolic enzyme and insulin receptor activity have been implicated in pathogenesis.³⁰ Resting and reactive autonomic (sympathetic/parasympathetic) disruption have been implicated in depression as well.³¹ Circadian, menstrual and seasonal biological/hormonal cycles have been shown to have a substantial effect on the relevant basic neurophysiological processes noted above.^32,33 Such observations underlie conditions such as premenstrual dysphoric disorder,³⁴ and treatments such as bright light therapy.³⁵