The past and future of integrated biopsychosocial whole-health perspectives in psychiatric rehabilitation

Abstract

Objective:

This article describes the historical, contemporary, and probable future roles of biosystemic whole-health perspectives in the evolution of psychiatric rehabilitation.

Methods:

We identify and discuss three examples of failures to fully consider the interaction of biological, psychological and social levels of functioning, which have led to significant barriers to recovery: Failure to account for physical morbidity in psychiatric disorders; lack of integration with modern understanding of inflammatory processes in psychiatric symptoms; and disregard for social and interpersonal factors.

Results:

Significant limitations in rehabilitation outcomes arise from failure to fully consider the molar (i.e., integrated) implications of molecular impairments and vulnerabilities, and vice versa. We articulate the consequences of molecular models of personal and social functioning as barriers to future research and clinical care, and propose looking beyond the traditional scope of psychopathology and boundaries of mental health services to reach a whole-health understanding of psychiatric disorder and disability, rehabilitation and recovery.

Conclusions and implications for practice:

The integrative biopsychosocial model is a particularly promising direction in the evolution of psychiatric rehabilitation, with strong clinical and theoretic implications that may guide much-needed change in policy and practice. Key to progress in our understanding of psychiatric disorder, disability, rehabilitation and recovery is a perspective on science and clinical practice that values integration of multiple domains of knowledge as much as analytic dissection of molecular (i.e., unitary) processes. Reforms must be expected at all levels of healthcare service systems, in practitioner training, administration, and social policy.

Public significance statement:

Our analysis examines the importance and impact of a holistic, integrated understanding of human functioning in the theory and practice of psychiatric rehabilitation. We provide recommendations to better integrate links between biological, psychological and social aspects of serious mental illness create barriers to recovery into theory, clinical practice and education, and policy reform.

There is broad consensus that our current healthcare system is subject to, if not defined by, considerable disparities and inequities that require systemic change. We here consider the integrative biopsychosocial model as a particularly promising direction in the evolution of psychiatric rehabilitation, with strong clinical and theoretic implications that may guide much needed change in policy and practice. In healthcare generally, and psychiatric rehabilitation and recovery specifically, integrative biopsychosocial perspectives include multiple epistemologies and domains of conceptual and experimental analysis ranging from physiology to psychopathology to social policy. These diverse domains are united and integrated by an understanding of the whole person, both as the ultimate focus of our attention, and as a complex system embedded within the many systems of our social and physical environments. For this reason, in healthcare, these approaches are often called whole-person care, or ‘whole-health’ for short (Kaslow et al., 2007).

Historical perspectives on the integrative biopsychosocial model

Whole-health is not a new idea. In the middle of the 20^th century, most notably in the work of Ludwig von Bertalanffy (1968), general systems theory revolutionized the life sciences through renewed attention to ecology, or the systemic relationships between organisms and their environments. Then, in 1977, George L. Engel’s landmark call-to-action paper warned of a ‘crisis in the biomedical paradigm’ (Engel, 1977). This ultimately served as his first formal proposal of what we know as today’s integrative biopsychosocial model, which in its earliest form at that time was known as the ‘biopsychosocial model of illness’ (Engel, 1977, 1982, 1997). Soon thereafter, general systems theory, biopsychosocial perspectives, and related integrated health ideas were further infused into psychiatry in the work of Judd Marmor (1994), energizing both social psychiatry and the community mental health movement. The growing realization that health is more than just the absence of disease spread whole-health frameworks throughout healthcare. By the end of the century, whole-health paradigms became systematized as salutogenesis, an alternative to the disease-oriented approaches that took on their modern form in the late 19^th and early 20^th centuries (Mittelmark et al., 2022). Meanwhile, Urie Bronfenbrenner (1981) showed that human development is itself an integrative biopsychosocial process, involving the connections and interactions between different systems and environmental factors that influence a person’s development, life, health, and wellbeing (Bronfenbrenner, 1994; Hertler et al., 2018; Rosa & Tudge, 2013).

In experimental psychopathology, Joseph Zubin and Bonnie Spring (1977)’s seminal essay attempted to explain discrepancies between evidence for a genetic origin of schizophrenia and evidence for environmental influences by proposing the concept of vulnerability, or the systemic nature of psychiatric disorders as developmental interactions between biological and environmental causes. Originally proposed as relevant to schizophrenia, vulnerability became central to our contemporary understanding of many psychiatric disorders. These whole-health-oriented approaches, which integrated biosystemic and developmental paradigms, made possible today’s consensus that disabling psychiatric conditions are predominantly neurodevelopmental, shaped by organism-environment interactions over the entire life span from pre-conception to death. By the end of the century, biosystemic neuroscience had also become the conceptual basis of clinical psychopharmacology practice (Muse & Moore, 2012) .

In parallel, when William Anthony (1977) translated the principles of rehabilitation psychology into the psychiatric context in the late 20^th century, the whole-person health view of recovery from disability was in step with the surrounding science. By the end of the century, there was an even broader revolution in the recovery movement, a transformation of public and professional attitudes toward psychiatric disorder and disability that was supported and promoted even by the U.S. government (Spaulding et al., 2016). The idea of recovery from psychiatric disability that took shape then, and which remains dominant today, is quintessentially biopsychosocial in nature. In psychiatric rehabilitation, recovery so conceived is both a goal and an ongoing process, and both can be effectively supported by integrative – that is, multidimensional, multidisciplinary, and multi-level – application of experimental psychopathology, systems neuroscience, neuro-immuno-endocrinology, cognitive psychology, sociology, disability studies, and beyond.

As rehabilitation psychiatry entered the 21^st century, whole-health perspectives became formalized across all aspects of research and clinical practice. The publication of Treatment and Rehabilitation of Severe Mental Illness (2003), a text now well known within the psychiatric rehabilitation and recovery community, represented emergence of an “integrated rehabilitation paradigm” in which biopsychosocial research on SMI was integrated into planning and implementing effective, recovery-oriented, psychiatric rehabilitation services (Spaulding et al., 2003) . This arguably field-defining text illustrates the crucial importance and applicability of the principles and values described across this manuscript, including the application of integrated biopsychosocial health models to psychopathology research, case conceptualization, treatment design, planning, implementation, and evaluation, as well as the importance of applying a bio-behavioral systems perspective to recovery-oriented, humanized, “whole-health” care to persons with SMI (Spaulding et al., 2003).

Today, the development of and recovery from psychiatric disease may be more readily understood in a multidimensional, biopsychosocial model than other aspects of physical health, which are more conventionally associated with a solely biological level of analysis and addressed with the biomedical model that represents the dominant paradigm of healthcare in the Western world. This may seem paradoxical, as so many major developments in treatment of psychiatric illness over the past century have been biological. Yet, critiques from the scientific and healthcare communities at large (e.g., Bandura, 1969, ch. 1; Bentall, 2009; Breggin, 1994; Ullmann & Krasner, 1965, pp 2-9; Whitaker, 2002) and from within the psychiatric rehabilitation and recovery community itself (Anthony, 1977; Paul & Lentz, 1977; Spaulding et al., 2003) have often cited the biomedical model’s disproportionate attention to molecular¹ physiological processes, to the neglect of more molar psychological and ecological ones.

The biological models historically associated with landmark ideas as genetic transmission of schizophrenia and dopamine-blocking drugs evolved before contemporary integrated biological system paradigms coalesced. At first, such ideas were deeply reductionist, echoing 19^th century expectations about finding “the” cause of mental illness as if it were a variety of progressive neuropathy, an “incurable brain disease.” Today, with the expansion of integrated biopsychosocial approaches to biomedical research, those ideas have expanded into broader understandings of the intricate dialectics between body and mind, between organism and environment, between person and community, between health and illness, between treatment and rehabilitation, and between disability, recovery and life itself. Through these frameworks, we better understand individuals as a person-system, shedding light on how genetic vulnerabilities interact with environments over the course of human development to produce disability, and how biological, psychological, and social factors need to be considered equally in formulating an optimal psychiatric medication regimen.

Today, these whole-health and biopsychosocial perspectives are more than an abstract ideal. Nevertheless, our reductionistic impulses persist, and fully integrated whole-health application of our biopsychosocial model is more difficult than just appreciating the theory. Despite field consensus and ample research evidencing the utility of whole-health perspectives in application to rehabilitation and recovery in research and care, their actual implementation continues to be subpar. Terms like ‘whole-health’, ‘biopsychosocial’, and “wellness” have become marketing buzzwords, which are now used liberally in descriptions of services, products, and research, regardless of the actuality of the extent to which they are being applied (Lorenz & Finley, 2020). We have substantial room for improvement in truly applying integrated biopsychosocial perspectives to recovery and rehabilitation at all relevant levels. Below, we consider several ways in which the future of psychiatric rehabilitation may be served by integrative biopsychosocial models and their application to research, clinical care, and policy: improving physical health disparities; preventing diagnostic overshadowing; increasing etiologic and prognostic assessments; and supporting interpersonal functioning.

The physical morbidity of disabling psychiatric disorder

One of the most grievous ramifications of our failure to effectively adopt whole-health frameworks is the pervasive health disparities seen in serious mental illness (SMI), with estimates of shorter life expectancy ranging from 12 to over 20 years (Ali et al., 2022; Brown, 1997; Chang et al., 2023; Laursen et al., 2019). The primary causes of this early mortality are not directly related to mental illness, such as suicide (Crump et al., 2013; The Lancet, 2016; Thornicroft et al., 2007). Rather, the causes are the same health conditions contributing to premature death in the general population (The Lancet, 2016; Thornicroft et al., 2007), including pulmonary diseases (Laguna-Muñoz et al., 2025; Ratcliffe & Halpin, 2025), cardiovascular, and metabolic conditions (Crump et al., 2013; Druss et al., 2000; Goff et al., 2005; Heiberg et al., 2019), and cancers (Crump et al., 2013; Kisely et al., 2013, 2023). Some of the disparity has been attributable to drug side effects such as anticholinergic-driven cognitive impairment (for typical antipsychotics and anticholinergics) and vascular and metabolic consequences of obesity (for atypical antipsychotics) (Hippisley-Cox et al., 2007; Tran et al., 2009), but these have arguably been reduced by progress in pharmacology (e.g., Stahl, 2013, pp. 173-180). The severe health disparities that remain can thus be largely attributed to a combination of lifestyle factors, exposure to chronic stress in the form of mental health stigma and discrimination (Chaudoir et al., 2013; Corrigan, 1998; Frost, 2011; Niedzwiedz, 2019), and most remarkably, to neglectful or misguided healthcare services (Jones et al., 2008; Kisely et al., 2023; Knaak et al., 2015; Rivera-Segarra et al., 2019).

Life expectancy in developed societies reflects a broadly dispersed healthcare system that performs some key public health functions, including public education on disease management and prevention, population-wide screening for general health risks, targeted screening in high-risk subpopulations, clinical training to ensure practitioners are trained to use these tools appropriately, and provision of infrastructure to make services accessible. However well-developed these resources may be in healthcare systems that serve the general population, they usually do not reach people with psychiatric disabilities (Druss et al., 2000; Goldman et al., 2018; Kilbourne et al., 2008; The Lancet, 2016; Thornicroft et al., 2007), even in countries with universal healthcare (Crump et al., 2013; Gandré & Coldefy, n.d.; Heiberg et al., 2019).

In one sense, this is a different kind of problem for the rehabilitation community. We are accustomed to problems that require scientific advances leading to new evidence-based practices. For this problem, however, we have empirically supported, cost-effective methods but face barriers to access them for our clients. Screenings for the most ubiquitous medical threats to longevity are in common use in the general population (American Diabetes Association, 2014; Arnett et al., 2019; Kavanaugh et al., 2000; LeFevre & Force, 2015; Smith et al., 2019), but not in populations with psychiatric disabilities (Druss et al., 2002; Jorm et al., 1999; Murphy et al., 2021). Contrary to stereotypes of mental illness, disparities in preventative healthcare services in people with SMI are not fundamentally due to disproportionate motivational neglect. For instance, in 2018, the American Cancer Society (ACS) recommended starting colorectal cancer (CRC) screenings at the age of 45 for persons with an average risk, followed by the US Preventive Services Task Force (USPSTF), and the Society Task Force on Colorectal Cancer (USMSTF) updating this recommendation in 2021 (People Ages 45-49 Are Not Getting Screened for Colorectal Cancer, n.d.; US Preventive Services Task Force et al., 2021). Despite the dangers of colorectal cancer, in 2016, around 26% of eligible adults under 50 years of age, accounting for an estimated 10.5% of new CRC cases, had never received CRC screening (US Preventive Services Task Force et al., 2021). In 2018, approximately 31% were not up to date on their CRC screening (US Preventive Services Task Force et al., 2021). Thus, you can see many Americans under the age of 50 do not aggressively seek out their recommended colorectal cancer (CRC) screening despite it being the third leading cause of death for both men and women, regardless of SMI status (US Preventive Services Task Force et al., 2021). There is also no lack of demographic-specific general health practice guidelines for populations with psychiatric disabilities (Drew & Funk, 2010). Instead, SMI-related physical health disparities persist because well-validated prevention and mitigation practices, including patient education and outreach, are usually not provided in healthcare systems that serve populations with psychiatric disabilities, commonly related to the barrier of mental illness stigma (Mittal et al., 2020; The Lancet, 2016).

In addition to policy reform, better training and education of health service providers in the application of the integrated biopsychosocial model would have a substantial impact simply by reducing neglect of general health maintenance and prevention. That is, by training practitioners to first recognize their patients with SMI as patients in human bodies – subject to the same forces that put all human bodies at risk for physical health conditions – we may mitigate some of the assumption that patients with SMI are not bound to the same requirements for preventative health screening and treatments. Such training would also help practitioners more accurately identify the role of psychiatric and non-psychiatric conditions in impaired cognitive and behavioral functioning and, ultimately, psychiatric disability – that is, counteract diagnostic overshadowing.

Diagnostic overshadowing provides a salient example of unreflective reductionism that focuses on one small component of an individual – in this case a history or presence of diagnosed mental illness – rather than the whole picture of that person’s health, which, in turn, contributes to failure to use standard medical screening and diagnostic tools even when available (Jones et al., 2008; Mason et al., 2010; Nash, 2013; van Nieuwenhuizen et al., 2013). It has long been known that practitioners tend to misattribute both psychiatric and non-psychiatric symptoms to a previously diagnosed psychiatric disorder, even when the symptoms are not included in the diagnostic criteria and have no known etiological connection to the diagnosed disorder (Hallyburton, 2022; Molloy et al., 2023; Nash, 2013). This too often leads to failure to detect and treat medical conditions in people with disabilities, with misattribution noted in conditions from renal disease (Preston et al., 2024) to dental disease (Clough & Handley, 2019)), and even incorrect determinations of legal cause of death (Landes et al., 2022). As another example described in detail in the next section, findings in our research group suggest that inflammation-related sickness behaviors can be viewed as depressive or negative symptoms in medical settings, contributing to diagnostic overshadowing in the presence of a historical psychiatric disorder diagnosis within a medical record (Beck-Felts et al., 2023, 2025; Speakar et al., 2023).

Diagnostic overshadowing has long been associated with healthcare providers’ errors in clinical reasoning influenced by unconscious negative bias (e.g., stigma related to SMI diagnoses) (Jones et al., 2008; Nash, 2013; Stoklosa et al., 2017; van Nieuwenhuizen et al., 2013). That is, practitioners “miss the complete diagnostic picture” (Molloy et al., 2023) when their internalized biases lead them to see SMI and not the patient with SMI. Improving training and education for practitioners may thus seem like the solution to diagnostic overshadowing, yet research on interventions targeting mental illness stigma and evidence-based practices shows limited impact on altering healthcare professionals’ attitudes (Mittal et al., 2020; Pelletier et al., 2016). Traditional solutions may fall short due to persistent stereotypes about mental illness among healthcare providers, even those specialized in mental health (Mittal et al., 2020). For example, a pervasive myth endorsed even among mental health providers is the belief that mental illness causes one to falsely or mistakenly report symptoms of unrelated illnesses (Graber et al., 2000; Shefer et al., 2014). Training programs should confront these biases actively—not only in the classroom but on the job via integration into basic competencies assessed in continuing education requirements or assessed by hospital systems as a marker of quality care provision.

However, beyond individual-level biases, other system-level factors must also be accounted for. Further compounding the negative effects of diagnostic overshadowing are the inconsistencies across health insurance systems and states, both in terms of inconsistent coverage across different policies and in the barriers posed to accessing essential screenings and treatments, such as pre-authorizations and appeals processes (Novak et al., 2018). Such inconsistencies contribute to delayed or denied care for the general public, but their effects are substantially compounded in SMI populations for several reasons. People with SMI are more likely to be reliant on either Medicaid or the lowest-cost policies (Han et al., 2015), which restrict access to many services and which experience higher rates of insurance denials (Hoagland et al., 2024). There is also evidence that when people with SMI are forced into high-deductible health plans, they manage overall out-of-pocket costs by decreasing their use of non-psychiatric healthcare services (including preventative care) in order to maintain psychiatric care coverage (Lu et al., 2021; Wharam et al., 2020). People with SMI are more likely to have executive dysfunction that interferes with tasks of daily living (Regev & Josman, 2020), which certainly includes difficulty engaging with a byzantine bureaucratic system designed (at least in part) to deflect appeals by being difficult to navigate (Yaver, 2024). And in a small but important minority of cases, issues arise when people with SMI cycle between jurisdictions of public, private, and institutional medical care, complicating care access across administrative dominions: for example, there is a well-known critical gap in coverage when people with SMI are discharged from forensic settings (where they are formally barred from being eligible for Medicaid) but have yet to undergo the months-long process of being (re-) approved for Medicaid coverage (Albertson et al., 2020; Morrissey et al., 2006).

Moreover, many insurance systems engage in their own form of diagnostic overshadowing, denying standard care for medical illness if a patient has a record of SMI (Roach, 2016; Sircar, 2017). That is, even if a provider recognizes the need for standard preventative care in their patient with SMI, insurance issues may mean that patient will not be able to access that care. In turn, biases arising from insurance issues and access disparities are transmitted to training environments, as outlined in the illustrative example below. Imagine a primary care physician treating a patient with a historical diagnosis of panic disorder (presently well-managed) who develops new and unexplained chest pain and shortness of breath. This provider is mindful of the higher likelihood that they will dismiss their patients’ symptoms because of their history of psychiatric illness (Graber et al., 2000; Shefer et al., 2014) and instead seeks to order the recommended diagnostic testing for cardiopulmonary disease. However, the insurance company repeatedly denies their preauthorization for that patient, declaring such testing as “medically unnecessary” in the context of the patient’s prior psychiatric history. Such denials take advantage of well-documented inconsistencies and vagaries in what is considered medically necessary in the context of patients with history of psychiatric care (Roach, 2016; Sircar, 2017), and in re-defining the patients symptoms as psychiatric, make their care more likely to be classified as out-of-network and subject to lower coverage (Mark & Parish, 2024). Over time, physicians may become discouraged from pursuing such tests, leading to a decline in seeking certain procedures/testing and, correspondingly, the quality of patient care. This can also impact the training of future medical professionals, who may be inadvertently taught to avoid pursuing specific procedures due to challenges in navigating complex insurance submission processes/systems. Most notably, practical strategies for navigating certain types of insurance submission and appeal processes are not adequately taught to newer professionals, further exacerbating the problem.

Thus, addressing diagnostic overshadowing must happen at a systems level to ensure equitable access to healthcare for all patients, including those with SMI. As mentioned above, continuing education guidelines can emphasize whole-health frameworks throughout clinical training. Federal guidelines mandating equal access to medical screenings, regardless of mental health history, and insurance plan coverage, could enforce best practices (Murphy et al., 2021). Implementing accountability measures, like required checklists for essential medical tests, may support this integration within the healthcare system. For example, compulsory implementation of enhanced primary care models and integration of medical care that include requirements for administering important preventative medical screening and services can be tailored to treatment environments serving SMI populations (Druss et al., 2001; Grove et al., 2021) .

The psychiatric rehabilitation and recovery community is very familiar with insufficient funding and resources, poorly trained personnel, incompetent and/or misguided administrators, public apathy, and political reluctance to invest in better services. But integrated biopsychosocial approaches to understand recovery from disability account for the importance of such molar systemic processes as service system design and administration in ensuring access to and participation in preventive healthcare. And, relative to reductionist models that (over) emphasize biologic contributions to physical health morbidity, integrative biopsychosocial models more readily support efforts to translate this understanding of the source of systemic inequities into policy action (McKay et al., 2012; Wade & Halligan, 2017). Regardless of whether the intersection of SMI and physical health conditions are considered as comorbidity (conditions that coexist alongside a primary diagnosis affecting one’s health), multimorbidity (coexistence of two or more chronic health conditions), or more general co-occurring health issues (any simultaneous health conditions that may or may not be chronic), molar frameworks better address the pathways and systems that syndemically give rise to both (Harrison et al., 2021; Vereeken et al., 2023).

The next example in our discussion identifies an adjacent problem – the interactions of inflammatory processes with symptoms traditionally interpreted as mental illness – illustrating similar pitfalls of reductionist models of SMI and the promise of integrated whole-health models in addressing these pitfalls. The same chronic health conditions captured by the health disparities seen in SMI are chronic medical conditions with underlying inflammation. As such, with the higher prevalence of undiagnosed or inadequately managed chronic health conditions, there comes an increased presence of chronic inflammation-induced sickness behaviors, which have significant ramifications for psychiatric rehabilitation and best practices in quality of care. Adequately considering the role of inflammation in SMI would reduce diagnostic overshadowing, among other benefits, by developing a better, more whole-person-oriented health and integrated understanding of the links between psychiatric disability and biological processes outside the nervous and endocrine systems.

Inflammatory processes, sickness behavior, and rehabilitation

The concept of psychophysiological processes associated with the body’s response to stress is, of course, not new (Selye, 1946, pp. 231-247, 358-398, 289-323, 231-247), but contemporary extensions of this work illuminates the surprising role of inflammatory processes in social behavior relevant to disability, rehabilitation, and recovery. While the earliest work posited inflammation as acting primarily within the immune system to assist in fighting pathogens and contributing to tissue repair, more recent research indicates that inflammation contributes to a complex network of central, autonomic, and endocrine system activity – collectively referred to as the neuroimmune system (Mayer et al., 2014). Key to the action of the neuroimmune system is the integration of inflammatory processes into diverse functions, including neurotransmitter activity and metabolism, neuroendocrine function, and regional brain activities relevant to mood, energy levels/fatigue, pain (both social and physical), and sleep disturbance (Bollen et al., 2017; Morrens et al., 2022). Psychiatric rehabilitation researchers and providers will recognize each of these as the hallmark symptom presentations that we seek to treat across various SMI diagnoses.

Inflammation is a highly generalized response to injury and/or stress, which involves the release of chemical messengers like cytokines, i.e. “signaling” molecules, including various interleukins (especially IL-6 and IL-1β), and tumor necrosis factor-α (TNF-α) (Dantzer & Kelley, 2007; Hart, 1988). Cytokines that originate outside the brain can act on brain function through multiple pathways, including direct transport across the blood-brain barrier (BBB); diffusion through areas lacking the BBB; and binding peripheral afferent nerves such as the vagal nerve, a key interface between the central nervous system (CNS) and the parasympathetic division of the autonomic nervous system (Dantzer, 2001, 2023; Konsman et al., 2000). Cytokines act on neurotransmission both directly, via activation of microglia, and indirectly, via modulation of monoaminergic, cholinergic, and endocannabinoid pathways (Miller & Raison, 2016). These downstream effects are not solely the result of primarily biological insults like infection – psychological stress itself can also trigger a neuroimmune response (Deak et al., 2017; Haykin & Rolls, 2021; Sequeira & Bolton, 2023), especially in individuals exposed to chronic adversity or possessing underlying vulnerabilities in immune regulation (Bower et al., 2022; Chiang et al., 2015; Cuevas et al., 2020; Kokkosis et al., 2024). Stress-induced immune activation may help explain the high prevalence of reported somatic symptoms in populations with mental health conditions such as SMI (Chiang et al., 2015; Ellis & Del Giudice, 2019; Nugent et al., 2015; Sequeira & Bolton, 2023), especially those from marginalized or underserved groups who experience elevated levels of chronic stress (Cuevas et al., 2020; Ford et al., 2021; Savransky et al., 2018).

The neuroimmune system also interacts with other subsystems such as the microbiota-gut-brain axis, which controls aspects of the digestive and metabolic processes. Neuroinflammation also alters both the production and activity of hormones relevant to metabolism and energy consumption (e.g., leptin), pain (e.g., prostaglandins), and emotion processing (e.g., cortisol) (Boemo et al., 2022; Yılmazer, 2024). Individuals with SMI show dysregulated neuroimmune activity that includes increased levels of various cytokines (e.g., in blood or cerebrospinal fluid), an upregulation of genes associated with dysregulation of cytokine pathways involved in inflammation and apoptosis as revealed by postmortem gene analyses of prefrontal cortex (Shelton et al., 2011), reduced natural killer cell activity, and lymphocyte proliferation (Blume et al., 2011; Dantzer et al., 2008; Schiepers et al., 2005; Zorrilla et al., 2001; Zunszain et al., 2012). Individuals at risk for dysregulated inflammation are significantly more likely to be diagnosed with schizophrenia (Williams et al., 2022). Specifically, inflammatory markers (e.g. cytokines) are associated with negative symptoms (e.g. blunted affect, alogia) and deficit syndrome symptoms (e.g. disorganization, derailment) (Goldsmith et al., 2018, 2019) in people diagnosed with schizophrenia. This may be associated with inflammatory effects on the brain’s subcortical reward processing systems (Goldsmith & Rapaport, 2020).

These patterns of immune dysregulation suggest that at least some of the cognitive, behavioral, and psychological symptoms of psychiatric disorders are attributable to inflammatory processes. Clinical expression of activated inflammatory processes includes disrupted cognition, malaise, fatigue, anxiety, loss of interest or pleasure (anhedonia), loss of motivation (avolition), increased pain sensitivity, and changes in appetite and sleep patterns – collectively termed inflammation-induced sickness behaviors (Dantzer & Kelley, 2007). Of note, the term “behavior” in this context refers merely to the output of immune action on the nervous system, and thus encompasses a variety of outputs that may not be immediately recognized as behaviors by the average behavioral specialist. For example, fever is a sickness behavior – that is, a response arising from the immune system’s modulation of the hypothalamus’ temperature regulation modules to induce elevated basal temperature (Dantzer, 2023; Evans et al., 2015; Piquet & Alvarez, 2021; Tizard, 2008). Sickness behaviors such as fatigue, anhedonia, social withdrawal, and cognitive slowing are evolutionarily conserved responses to immune activation that are often mistaken for symptoms of psychiatric disorders (Dantzer, 2009, 2023; Dantzer & Kelley, 2007). Understanding their biological roots may help explain why certain populations, particularly those with depression and other forms of SMI, are frequently labeled “treatment-resistant” when conventional psychiatric and psychosocial interventions fail.

Like all humans, people with psychiatric disorders can get physically sick, and the well-documented chronic stress and deprivation to which people with psychiatric disabilities are often subjected may activate neuroimmune responses even in the absence of a diagnosable disease or observable injury (Anisman, 2009; Chrousos, 2000; Fulda et al., 2010). Chronic inflammation thus represents a critical bridge between sustained physiological dysregulation and the onset or exacerbation of psychiatric disorders. While acute inflammation serves an adaptive purpose in mobilizing immune resources to combat infection or injury, chronic inflammation exerts a persistent influence on the body and brain, often without an identifiable pathogen or acute injury (Allan & Rothwell, 2003; Liu et al., 2012; Lucas et al., 2006; Straub, 2012). Chronic inflammation leads to long-term alterations in immune signaling, metabolic regulation, neuroendocrine activity, and central nervous system function – collectively, the immune components of allostatic load (see below; (Juster et al., 2010). In the context of psychiatric rehabilitation, this biological environment can foster the development of mood dysregulation (Capuron et al., 2004; Pollak & Yirmiya, 2002), cognitive impairments (Cunningham & Hennessy, 2015; Reichenberg et al., 2001), and maladaptive social behavior, all of which are hallmarks of SMI (Eisenberger, Berkman, et al., 2010; Eisenberger et al., 2009, 2017; Eisenberger, Inagaki, et al., 2010).

The burden of chronic stress and inflammation is not evenly distributed across populations. Vulnerable and marginalized groups – racial and ethnic minorities, sexual and gender minorities, those with disabilities, low-income populations, people living with SMI, and those living at the intersection of all of these – are disproportionately exposed to chronic psychosocial stressors that activate immune and neuroendocrine pathways. These stressors include many social determinants of health and environmental factors like experiences of discrimination, systemic racism and other forms of institutionalized stigma, poverty, housing or food insecurity, trauma, and social exclusion (Schulz et al., 2012; Szanton et al., 2005). Over time, the cumulative physiological wear and tear resulting from repeated stress activation and consequent dysregulation of the body’s stress response (such as hyperactivation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system), known as allostatic load, exerts a profound influence on immune system functioning and contributes to a chronic inflammatory state (Guidi et al., 2020). Chronically elevated levels of circulating cytokines and other inflammatory products can damage tissues, impair neuroplasticity, and disrupt neurotransmitter systems, particularly those involved in dopamine and serotonin signaling (Cai et al., 2005; Capuron et al., 2012; Edman et al., 2008; Müller & Schwarz, 2007; Prajapati et al., 2015; Zhu et al., 2010). These changes set the stage for a range of psychiatric symptoms described above, especially those “resistant” to conventional psychosocial or pharmacological interventions. Thus, the significance of sickness behaviors among people with psychiatric disabilities may well be in the same domain as the previously discussed diagnostic overshadowing.

None of these processes are exclusively associated with specific psychiatric diagnoses, and are therefore often termed “transdiagnostic” in contemporary healthcare argot. In reductionist views of psychiatric disability, problems not generated by molecular brain abnormalities associated with specific diagnoses are annoying distractions, and “patient role performance” is often merely a euphemism for malingering. That is, sickness behaviors may be understood as a nonspecific product (or more properly, an unspecified product) of the psychiatric disorder itself (despite evidence noted above regarding the likely direction of causality with regards to inflammation). This makes inflammation-mediated sickness behaviors especially vulnerable to diagnostic overshadowing and misinterpretation. Put simply: inflammation-induced sickness behaviors likely contribute to the overall symptom load across a range of psychiatric disorders, but patients with these disorders are significantly less likely to be afforded consideration of their physical health as a major driver of their psychiatric presentation. What is more, research on sickness behavior as an expression of immunological processes shows that the impairments in personal and social functioning may be neither the sole product of social learning (i.e., the “sick role”) nor the psychiatric disorder itself. There is, therefore, room for improvement in rehabilitation tools for addressing amotivation, despair, hopelessness, social anxiety, and self-isolation by identifying and treating immunogenic sickness behaviors when they occur in people in recovery.

Psychiatric rehabilitation – and the medical system more broadly – critically needs a more complete understanding of sickness behaviors and the “disabled patient” role from a biopsychosocial framework. If specific sickness behaviors correlate more highly with certain psychiatric symptoms than others, this would improve best practice guidelines by serving as “red flag symptoms.” Increases in these symptoms could then help prompt medical screenings and other interventions or procedures that ultimately reduce health disparities in the uniquely vulnerable (Ali et al., 2022; Chang et al., 2023; Drew & Funk, 2010; The Lancet, 2016; Thornicroft, 2011). A transdiagnostic model of sickness behavior may also shed light on “treatment resistant” subpopulations who tend to demonstrate higher inflammatory profiles than those who better respond to current best practices in psychopharmacological and psychosocial treatment (Gaynes et al., 2020; Kane et al., 2019; Orbe & Benros, 2023; Strawbridge et al., 2019). For instance, inflammation-modulating treatments such as with corticosteroids are well known to produce adverse psychiatric effects including disturbances in mood, cognition, behavior, and even frank psychosis (Gostoli et al., 2025; Kazi & Hoque, 2021). Treating such patients with antipsychotics or psychosocial approaches, rather than attending to the underlying immunoendocrine drivers of the symptoms and other functional impairments, would lead to poor outcomes and the belief that the patient is “treatment resistant.”

The possible implications of generalized inflammation for vulnerability, as opposed to frank illness and disability, are shown in findings from our lab in a study using a non-clinical sample of emerging adults (ages 18-35). We measured participants’ sickness behaviors via Andreasson et al.’s (2018) Sickness Questionnaire, a self-report instrument of participant’s subjective experience of sickness. Prior studies validated that scores on the sickness behavior survey are strongly correlated with systemic inflammation levels following injection with a nonpathogenic antigen (endotoxin). Sickness behaviors in our sample were associated with a multitude of psychiatric symptom presentations at the construct level, including depression, anxiety, attenuated negative and positive psychotic symptoms, executive dysfunction, sleep disturbance, and feelings of social disconnection. Regression analyses demonstrated that greater endorsement of sickness behaviors predicted attenuated negative psychotic symptoms, even when controlling for sex/gender and depression (Beck-Felts et al., 2023). Interaction analyses demonstrated insomnia and physical activity moderated the relationship between sickness behaviors, depression, anxiety, and attenuated positive psychotic symptoms (Speakar et al., 2023).

After more than a century of analyzing the biological level of systemic functioning to find the causes of psychiatric disorder, we are finding biological processes like generalized inflammation, quite different from those familiar ones most proximally associated with frank illness, yet comparably implicated in producing disability. Incorporation of these less familiar biological-level factors into our prevention, treatment, and rehabilitation models and methods is now the task we face. We are led to understand vulnerability itself as a complex interplay of biological, cognitive, behavioral, and socioenvironmental factors unfolding over time.

Interpersonal functioning, social support, health, and recovery

Our third example considers another link between relatively molecular biosystemic processes and the social and interpersonal level. One of the striking features of the ways in which sickness behaviors manifest is directing, and being directed by, social isolation (Eisenberger et al., 2009, 2017; Eisenberger, Inagaki, et al., 2010). The urge to temporarily self-isolate when experiencing significant inflammation has evident evolutionary advantages, limiting both the impact of contagious disease and other burdens on the surrounding community, and limiting contact with others who may introduce additional pathogens (Eisenberger et al., 2017; Hennessy et al., 2014). However, when experienced chronically (e.g., in response to the chronic stress of mental health-related discrimination), such behaviors may lose their adaptive element.

In a more general sense, one of the foundational ideas of evolutionary medicine is that diseases, including psychiatric disorders, are often the failure of a system component evolved for a specific purpose in a specific environment that was different from the environment in which it is currently living (Baron-Cohen, 1997; Trevathan et al., 1999). For example, in humans, type II diabetes is understood to be a consequence of contemporary diets and lifestyles for a metabolic system that evolved in early human environments and conditions. Depression can also be understood in this perspective as originally an adaptive response to resource loss requiring severe economic restrictions in physical activity (Nesse, 2000). As primordial human culture evolved, biological, psychological and social processes interacted to produce the complex syndromes of dysphoria, suppression of cognitive and motor activity, social aversion and avoidance that we now designate with such terms as “depression” or “negative symptoms of schizophrenia.” Most recently, there has been a flood of new research, outside the traditional context of psychiatric symptoms, showing that social isolation and its most direct consequences, especially loneliness, are major barriers to both psychological and physical health (Leigh-Hunt et al., 2017).

Understanding the myriads of biological, psychological, environmental, and social factors that contribute to social isolation should become a priority for psychiatric rehabilitation. An exploratory study of developmental and psychological pathways to social isolation recently conducted in the authors’ lab (Stinson et al., 2022) demonstrates the promise of such an understanding. A large non-clinical sample of young adults were screened for schizotypy, a well-known construct associated with genetic vulnerability to eventual onset of schizophrenia-spectrum disorders. They were then administered an array of measures of social cognition, affect, and social connectedness. Participants with high schizotypy scores reported low levels of cognitive empathy (understanding others’ perspectives and emotional states), distress tolerance (ability to tolerate rather than avoid or escape even mild negative affect), interpersonal responsiveness, and social connectedness, and high levels of alexithymia (difficulty identifying and describing one’s own emotional states) and emotion contagion (difficulty discriminating one’s own emotional responses from those observed in others). In addition, structural equation modeling revealed separate pathways - presumably congenital characteristics acquired later in life – leading to social disconnectedness in adulthood. Individuals with primarily positive schizotypy (traits corresponding to the “positive symptoms” of schizophrenia spectrum disorders, such as attenuated positive psychotic symptoms) reported abnormal levels of interpersonal responsiveness, emotional contagion, and cognitive empathy, but only cognitive empathy lay on a direct pathway to poor social connectedness. For individuals with negative schizotypy traits (e.g., amotivation, blunted affect), the pathway to poor social connectedness also included alexithymia. Individuals with disorganized schizotypy traits tended to score more abnormally on all measures, but their pathway to social disconnectedness included both distress intolerance and alexithymia, as well as cognitive empathy.

Much remains to be done to articulate the distinct traits, habits, and other characteristics that lead from congenital or early-acquired vulnerabilities to impaired psychological functions to social connectedness, but already the data suggests that different individuals need different kinds of help, perhaps even at different stages of development, to avoid or overcome the consequences of social isolation. In a secondary prevention paradigm, where vulnerable individuals are identified for special preventive interventions before they become ill or disabled, this could mean therapy directed at abilities associated with relatively early development, such as emotion recognition and distress tolerance. In a tertiary prevention paradigm, where the goal is to reduce disability, or in recovery-oriented rehabilitation, where the goal is to reverse it, this means applying treatments we already have (Compton & Shim, 2020; Hofmann et al., 2011; Kennedy & Franklin, 2002; Zeifman et al., 2020) in a more selective way, based on what we understand about the multiple “causes” of social isolation among different individuals in the broader disabled population. The individual factors make good treatment targets, but they have limited value by themselves. They are made meaningful by a whole-health understanding of their role in producing the global problem of social isolation.

Conclusion

Integrated whole-health science is providing new understandings of psychiatric disability and ways to overcome barriers to recovery. At the policy level, ensuring equitable access to standard health maintenance resources is essential to reduce the unacceptable disparity in health and longevity between people with and without psychiatric disabilities. Clinically, healthcare professionals must be better trained to avoid diagnostic overshadowing and to address transdiagnostic biological factors that compromise recovery. Systems-level reform is also needed to dismantle economic, administrative, policy, and even socio-political barriers within healthcare. At intrapersonal levels, interventions that support social participation and affiliation can offset the effects of other vulnerabilities and disabilities. We can see progress today in all those domains. Despite the promise of future progress, however, we must also heed past missteps of an overly narrow, molecular focus. The discovery of molecular underpinnings of psychiatric disorder and disability must be understood in the context of more molar expressions of our patient’s lived experience of recovery. Even when we eschew reductionism and reach for more integrated understandings, we overlook key determinants of health such as general medical morbidity, immunoendocrine dysregulation or the cognitive tolls of social isolation, simply because we have historically associated them with only a single level of the biosystem. Our progress will depend on uniting these perspectives, from molecular to molar, in pursuit of equitable psychiatric rehabilitation.