Introduction
Bipolar disorder (BD) and more generally affective disorders are progressive conditions. BD may present with progressive central and peripheral biological alterations, as well as a heterogeneous clinical course of the illness. The trajectory of major affective disorders is characterized by specific lifetime epochs, including early lifetime trauma, childhood precursor disorders, clinical symptomatic state (i.e., recurrent depressive and manic episodes alternating with euthymic phases), suicidal behaviors, brain alterations stages, neurocognitive deficits, and a residual stage with functional impairments. The staging model (Fig. 1) defines clinically evident points in the course of a disease that are detectable, reflecting a certain level of severity in terms of risk of loss of autonomy, and which could be valid predictors of prognosis or therapeutic responses 1. After Fava and Kellner’s preliminary work in 1993 2 developing clinical staging models for major psychiatric disorders based on the longitudinal development, major efforts have been made to understand BD through linking the pathological rewiring of the brain that takes place in parallel with clinical progression to the stages of the disorder. In contrast to other branches of medicine, biological staging in psychiatry is hampered by a lack of clear nomenclature regarding clinical staging, due to the fact that both etiology and pathophysiology of psychiatric disorders are still largely unknown. Nevertheless, several clinical staging models of BD have been developed over time since Fava and Kellner’s first study 2. Most of these models focus on traditional diagnostic categories 3-7, while others are transdiagnostic models that attempt to capture the non-specific and fluid early stages of the disorder 8. Transdiagnostic staging models are probably optimal for the study of the at-risk and prodromal phases, while disorder-specific models might be useful to understand the late stage of the full expressed disorder 9. Criticisms concerning the disorder-specific approach argued that the model is more applicable to the late stages with an established illness, and it does not incorporate an “at risk” phase, which is a critical element of all medical models of staging 7. Critics of the transdiagnostic model argued that it may promote a hierarchical model which is biased toward psychotic disorders over other disorders given that operationalization of stages are more reliant on functional level rather than phenomenology 7. Staging affective disorders could be helpful in delivering tailored treatments to the patient. By using the staging model, clinicians may weigh factors such as patients’ social support and their adaptation, resilience and reaction to previous conflicts, threats or losses assess motivation and compliance with treatment, modeling the choice of the intervention. The traditional nosological diagnosis of affective disorders emphasizes a cross-sectional description of syndromes and is based on clusters of symptoms and does not take into consideration some features, including family history of mental illness, prodromal patterns, traumas, severity of the recurring pattern of the disease, suicidal behaviors, neurocognitive deficits, and deteriorated outcome characteristics. As such, affective disorders are not stage-defined, although diagnostic criteria based on staging may provide more appropriate and targeted treatments to prevent further episodes and progression into the later stages, which are characterized by functional and cognitive decline 3. In this context a relatively neglected, clinical important issue, is the study of prodromal symptoms in mood disorders. Appraisal of prodromal symptoms may be of practical value providing challenging insights into the pathogenesis and course of major affective disorders in a longitudinal perspective, according to a staging model of the illness. The definition of a prodromal phase would benefit from the joint use of symptom identification, biomarkers, and neuroimaging 10.
Prodromal phase
The term “prodrome” derives from the Latin word prodromus, which in turn stems from the Greek prodromos. In medicine, prodromes can be identified with the early symptoms and signs of a disease that differ from those of the acute clinical phase. The prodromal phase refers to the time interval between the development of prodromal symptoms and the onset of the characteristic manifestations of the fully developed illness 11. Recognizing and detecting the prodromal symptoms of affective disorders may lead to a more timely and effective treatment of relapse and recurrence 11. The construct of prodromes is in line with a staging model that considers the longitudinal development of illness 2. This model defines the extent of progression of a disorder for an individual at a particular point in time (e.g., prodromal, acute, and residual phases). Until the 1990s, staging was largely neglected in psychiatry, in contrast to other medical disciplines. Over the time, the construct of prodromes and staging of affective disorders has been increasingly recognized as important components of clinical assessment. The concept of prodromes in mood disorders has been known for a long time thanks to the first studies of Hays in 1964 12, Hopkinson in 1965 13, Winokur and Paykel in 1976 14,15 and Young and Grabler in 1985 16, among others. It was with studies from the late 1980s onwards that standardized methods began to be used for the assessment of prodromal symptoms allowing a definition of the construct of prodromes in mood disorders. The study of Fava et colleagues 17 was one of the first studies to focus on the prodromal symptoms of depression using a semi structured interview. Their study revealed that all of the depressed patients displayed at least one prodromal symptom, particularly generalized anxiety and irritability and other non-specific symptoms like impaired work and initiative, fatigue, and initial and delayed insomnia 17. However, the early stages of mood disorders are diffuse and non-specific, and several relatively non-specific psychopathological presentations have been reported as antecedents to the full symdromal onset. In line with these preliminary studies, reviews about prodromal symptoms in symptomatic patients identified several, although not specific, prodromal symptoms in four specific areas: cognitive, emotional, physical and psychomotor 10,11. Prodromal symptomatology exists before the onset of unipolar depression and the overall rates of prodromal symptoms ranged from 26 to 100% 10. Anxiety, tension, irritability, reduced energy, fatigue, sleep disturbances, and somatic complaints were the most commonly reported prodromal symptoms 10. Regarding the duration of the prodromal phase, the results are influenced by the different methodological tools used, and it ranges from less than a month to several years. However, the mean durations are long enough to indicate that there may be the possibility of effective early interventions in many patients.
To better investigate and study the prodromes of mood disorders, a series of prospective cohort studies have taken place in more recent years. Of particular relevance in this area are the studies of Angst et al. 18 and Tijssen et al. 19. These studies recruited large community samples and conducted follow-up assessments for up to 15 and 10 years respectively. The Zurich cohort study 18 investigated bipolar spectrum disorder (BSD), rather than BD I. Moreover, the sample was enriched by identifying high-risk subjects (high scores on the Symptom Checklist-90R) and included a control group of a sample of average scorers on the same checklist. Tijssen et al. 19 recruited a sample of young adults at random from the population register for the Munich area by excluding subjects with symptoms attributed to alcohol or substance use, and subjects with a past or current diagnosis of BD at baseline. Both studies provide evidence of clinical features/symptoms preceding the onset of BD. The most commonly reported putatively prodromal features were affective swings and depressive mood. Particularly in the study by Angst et al. 18, mood swings (frequent ups and downs), probably due to a lability and/or immaturity of the mood-regulating system, was the strongest risk factor for the subsequent diagnosis of a BSD, greater even than a family history of mania. This result was in agreement with a previous study of Akiskal et al. who found that mood lability was also the strongest predictor of a diagnostic change from unipolar to BD II disorders in a 11-year prospective study of 559 patients 20. A recent systematic literature review has further confirmed this finding, showing that longitudinal studies demonstrated a significant association between prospectively identified affective lability in cohorts without BD and subsequent diagnoses of BD or BSD 21.
Affective liability is a sudden, exaggerated, unpredictable, and inappropriate change in emotion. It could be defined as a tendency to experience frequent, rapid fluctuations of intense affect, as well as the inability to regulate these fluctuations or their behavioral sequelae 22. Whilst the clinical significance of this instability is now recognized even in the DSM 5 criteria for BD and others mood and related disorders, very little is known about underlying neural mechanisms of mood instability. Difficulties in regulating mood are often also seen in youth at risk to develop mood and anxiety disorders further supporting its predictive nature. Preliminary evidence shows that a combination of clinical and neural measures at MRI scan could predict future affective lability factor scores in youth at risk for BD and thus may indicate risk for future BD 23. Particularly, future affective lability factor scores such as mixed/mania, irritability, and anxiety/depression, could be predicted by neural function and gray matter structure in brain regions supporting brain reward and emotion processing 23. This is in agreement with studies showing alterations of cortical thickness in adults with BD, BD at-risk youth and adults, and depressed youth relative to healthy controls 24. These findings are too small and inconsistent to serve as diagnostic makers, they might be of particular relevance for within-subject comparisons in the context of neurodevelopment and longitudinal staging of BD. Since there is a substantial heritability of cortical thickness, stress response and cerebral glutamate levels 24, neuroimaging and genetic tools and clinical assessements might be combined to increase their clinical utility. For example, reduced cortical thickness along with glutamatergic abnormalities found in BD and subjects at risk, could be the result of the underlying susceptibility genes (i.e. glutamatergic system) and environmental factors (i.e. stress) during life, acting on the fragility of the cortical structure leading to the clinical expression of BD 24,25. The possibility of being able to identify, by means of objective data (i.e., neuroimaging, genetics, electrophysiological) combined with through clinical assessments, subjects at risk of developing future affective lability and consequently a possible BD, opens the door to early intervention in these subjects. Particularly, younger patients enhanced neuroplastic potential and targeting these patients at early stages of illness is beneficial in preventing cortical deterioration. These early interventions may take the form of psychotherapeutic, pharmacological and/or social interventions, within the broader framework of a holistic intervention. For instance, physical activity has been shown to be able to induce neuroplasticity in medial temporal cortical regions in subjects with early psychosis 26.
Apart from symptomatic prodromes such as affective lability, it is necessary to know and identify the social risk factors of mood disorders. In a holistic bio-psycho-social approach to the staging and development of mood disorders, the clinician should always pay attention to various environmental factors that cumulatively to the genetic risk, favor the onset of the disorder. In this context, research on monozygotic twins discordant for mood disorders attempted to demonstrate how different environmental events can trigger the development of a mood disorder. As is well known, among the most important factors are intimate love relationship, degree of planfulness, occupational stressors and major traumatic life events 27,28. Typically, monozygotic twin studies tend to agree that the differences between twin pairs grow substantially over the human life span, emphasizing the importance of cumulative environmental experiences. Most of this research pointed out how temperamental differences can magnify themselves across the life courses, describing a process called cumulative continuity, i.e. individuals actively seek out environments that are compatible with their dispositions 29. This means that individuals’ affective temperaments can lead them to select environments that, in turn, reinforce and sustain those same behavior pattern across the life course through the progressive accumulation of its own consequences 27.
Hence the importance for the clinician to work with the patient in the clinical practice in order to identify symptomatic prodromes and social risks factors to develop effective strategies to carefully manage them. It is recommended to monitor the person’s mental state, possibly with new digital assessment methods, and encourage a healthy lifestyle, be knowledgeable about the symptoms of the disorder, and know when to ask for professional help. Nowadays, among the various tools available to the clinician to monitor a patient’s daily life and response mechanisms to stressors, we can mention the ecological momentary assessment (EMA). EMA describes a type of data collection that allows clinicians and researchers to gather detailed insight into the daily lives of patients by inquiring about the subjects’ mental state in the moment, avoiding memory recall bias. EMA techniques provide methods by which a patient can report on symptoms, affect, behavior and cognitions close in time to experience, and these reports are obtained many times over the course of a day 30.
Discussion
Research on prodromal symptoms and staging of mood disorders has not yet provided the expected impact in clinical practice. It remarks that the traditional, linear and oversimplified medical models in psychiatry should be supplanted by an updated multifactorial model. It is necessary to carefully consider the predisposition to disease, the time and manner of symptoms presentation, multiple disease forms, variable adaptive responses, and the role of social and cultural factors. One of the main difficulties with this approach is where to locate prodromal symptoms that precede the first depressive or manic episode and how to describe subthreshold affective syndromes. To date, still, we do not have a clear definition of the stages of mood disorders, prodromal symptoms are still too unspecific, and we have no specific personality trait predicting affective disorders. While the recognition of prodromal symptoms may help the clinician to psycho-educate the patient and his family, there are no specific pharmacological treatments in specific stages. The data respect specific treatments in specific stages are still too scarce and this is especially pertinent for early subthreshold stages of illness. A central issue in research into the prodromal symptoms and staging of mood disorders is the great phenotypic heterogeneity of these and the absolute lack of biomarkers. In contrast to other branches of medicine, psychiatry suffers from a diagnostic and classification system that is not based on pathophysiology and etiology, being dependent on nosological tradition, expert consensus, psychometric reliability, and clinical utility. In this context, the definition of stages in affective disorders would benefit from the joint use of symptom identification, biomarkers, and endophenotypes 24,31,32. Dissecting psychiatric macro phenotypes into biologically valid components presumes the ability to make diagnoses more certain, specific, and amenable to tailored treatments. Particularly, research on endophenotypes is of a great value as it has the merit to reduce heterogeneity by defining biological traits that are more direct expressions of gene effects. The search of endophenotypes has a prevention potential as they can be used to identify individuals who are at risk of developing a mental disorder. Naturally, endophenotypes could contribute to a clinically useful reclassification that will improve the treatment of mental disorders 24. To date, there is considerable evidence to support a possible developmental etiology of mood disorders. Particularly, the presence of abnormalities already presents at the beginning of these disorders and even in young at-risk subjects confirms this hypothesis. For instance, there is substantial evidence that early white matter abnormalities (WMAs) with resulting fronto-limbic dissociation play a central role in the pathophysiology of BD 33. Starting from the fetal period, the interplay between environmental risk factors such as stress and infections, and the genetic susceptibility of different systems like immune, circadian and glutamatergic systems among others, shape a vulnerable brain. Early WMAs might be the result of this vulnerable brain on which new stressors are added in young adulthood which favour the onset and progression of the full disorder as the brain does not have the appropriate resilience to resist 24. Importantly, studies on BD show that these WMAs may be at least partially normalized by medications via glutamatergic neuroplasticity processes. Interestingly, mood stabilizers have well-documented neuroprotective and neurotrophic effects in vivo and in vitro. For instance, long-term lithium treatment increases total grey matter volume 34, enhances levels of N-acetyl-aspartate, a marker of neuronal viability 35; and increases diffusion tensor imaging (DTI) measures of axial diffusivity (AD) in several white matter fibre tracts, including interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections in the brains of BD patients, correlating with its clinical efficacy 36. This suggests that lithium and other drugs might counteract the detrimental influences of BD on white matter structure, contributing to the functional integrity of the brain 36. Taken together, these data encourage research on the use of specific types of medication, psychoeducation, and psychotherapy from the earliest stages of the disorder.
Research on prodromal symptoms and staging of mood disorders introduced by Fava & Kellner in the 1990s 2 is still relevant and deserves more attention. There are still several unmet needs. Despite great advances in neuroimaging, structural, and functional neuroimaging explain not more than 2% of the variance in mood disorders, so it is of little use for diagnosis 37. Hence the growing importance of combining different biological markers such as genetic risk scores, neuroimaging, and psychosocial assessments in disease prediction algorithms. As already discussed, this could be done even better by reducing phenotypic heterogeneity through the study of endophenotypes. This would make it possible to assess the effect of various combined treatments (e.g., drugs, psychotherapy, psychosocial treatments) on the progression of mood disorders and establish the risk/benefit ratio of starting treatment at an early stage of the disorder. New treatment approaches capable to enhance neuroplasticity and neuroprotection, working on the glutamate system, may enhance psychosocial interventions and deserve more attention as a potential treatment in the early stages of the disorder.
Conclusions
The timely recognition of prodromal symptoms and environmental crisis factors in individual patients may facilitate early intervention upon relapse, since prodromal symptoms of relapse tend to mirror those of the initial episode 17. This could be implemented by having a history of illness progression, and investigating prodromal symptoms when the patient is judged as being in remission. After the acute phase, it may be difficult to assess whether partial or full remission occurred without knowing the patient well before the onset of the disorder. Residual symptoms may be caused by a partial persistence of the disorder or an aggravation of a pre-existing abnormal personality traits. Such an aggravation may be caused by various factors like, for instance, life events and stressors 2. This makes it possible to significantly shorten the duration of the episode 38 by initiating pharmacotherapy and/or psychotherapy when the same symptoms appear again, before the full manifestations of the disorder. Moreover, according to a staging method 2 research suggested consistency of the prodromal symptom profile and duration within individuals across depressive episodes and similarities between prodromal and residual symptoms of the same depressive episode 10. This implies that treatment directed toward the residual phase (i.e. sequential model) might provide long-term benefits in preventing relapse compared to just one course of treatment 39. Before discontinuing or decreasing medication on discharging the patient from psychotherapy, psychiatrists may educate patients and their families to be particularly aware of the specific symptoms that preceded the illness episode and rapidly notify the psychiatrist. Psychoeducation of the patient, based on the explanation of how to recognize prodromes and the benefits and risks of treatments, has shown to improve compliance and outcomes as well as reduce relapse in affective disorders.
Acknowledgments
This work was supported by #NEXTGENERATIONEU (NGEU) and funded by the Italian Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)
Conflict of interest statement
The authors have no conflicts of interest to declare.
Funding
The authors have no funding to declare.
Author’s contributions
The authors have contributed equally to this paper.
Figures and tables
FIGURE 1. Possible stages pathways from in utero to adulthood. This figure describes a heuristic model to link developmental stages of mood disorders with the timing of the biological and psychosocial underpinnings of etiological and pathophysiological events. ACC anterior cingulate cortex, EMA Ecological momentary assessment
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