Bipolar I Disorder (BD-I) is a severe, recurrent psychiatric condition arising from intricate interactions between genetic, environmental, and biological factors. Immune dysfunction and neuroinflammation are increasingly recognized as contributors to its pathogenesis. We present the case of a 51-year-old male with BD-I, selective immunoglobulin A deficiency (SIgAD), and iatrogenic hepatitis C infection, whose clinical course highlights the complex neuroimmune and affective interplay underlying mood disorders. His psychiatric history includes recurrent manic episodes with psychotic features, initially triggered by interferon-alpha therapy, a known immune activator. Early life adversity, including paternal loss and the psychosocial burden of premature caregiving, intersected with chronic immune dysregulation from SIgAD and iatrogenic hepatitis C, potentially fostering neuroinflammatory priming. The trajectory of his illness is consistent with the affective sensitization (kindling) model, where initial episodes were stress-linked, but subsequent recurrences emerged autonomously. Additionally, a traumatic brain injury during a manic state likely added neuroanatomical vulnerability without altering the primary affective phenotype. This case underscores the relevance of immune-inflammatory mechanisms in BD-I and highlights the importance of integrative, biopsychosocial approaches to both diagnosis and management, especially in medically complex patients.
El Trastorno Bipolar tipo I (TB-I) es una enfermedad psiquiátrica grave y recurrente que surge de complejas interacciones entre factores genéticos, ambientales y biológicos. La disfunción inmunológica y los procesos neuroinflamatorios son cada vez más reconocidos como elementos relevantes en su patogénesis. Presentamos el caso de un paciente varón de 51 años con TB-I, deficiencia selectiva de inmunoglobulina A (IgA) e infección por hepatitis C de origen iatrogénico, cuya evolución clínica ilustra la compleja intersección neuroinmune y afectiva que subyace a los trastornos del estado de ánimo. Su historial psiquiátrico incluye episodios maníacos recurrentes con síntomas psicóticos, inicialmente precipitados por tratamiento con interferón-alfa, un potente activador inmunológico. La adversidad temprana, marcada por la pérdida paterna y la asunción precoz de roles de cuidado, se combinó con la disfunción inmune crónica derivada de la deficiencia de IgA y la hepatitis C, favoreciendo un estado de neuroinflamación persistente. La evolución clínica es coherente con el modelo de sensibilización afectiva (kindling), en el que las primeras recaídas fueron reactivadas por estresores externos, mientras que los episodios posteriores surgieron de forma autónoma. Este caso subraya el papel de los mecanismos inmuno-inflamatorios en el TB-I y refuerza la necesidad de un enfoque diagnóstico y terapéutico integrador.
Bipolar I Disorder (BD-I) is a chronic, recurrent psychiatric illness shaped by a complex interplay of genetic vulnerability, environmental adversity, and biological perturbations.1,2 Growing evidence highlights the role of immune dysregulation and neuroinflammatory processes in the pathogenesis of mood disorders, potentially linking early life stressors, autoimmunity, and neuroprogression to the illness course.3,4 Here, we present a case of a 51-year-old male with BD-I whose psychiatric trajectory is marked by immune-related comorbidities, traumatic experiences, and recurrent manic episodes, illustrating the multifactorial pathophysiology underlying bipolar disorder.
Case presentationThe patient, a 51-year-old caucasian male and the eldest of three siblings, has a longstanding diagnosis of BD-I. He was admitted to our psychiatric unit during his fourth manic episode, which displayed clinical characteristics highly congruent with his prior affective decompensations. He reported no family history of psychiatric or neurological disorders.
Beyond his psychiatric condition, the patient's medical history is significant for selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, characterized by reduced or absent IgA with preserved IgG and IgM levels. The immunological vulnerability conferred by SIgAD predisposed him to recurrent respiratory and gastrointestinal infections throughout childhood and adolescence, shaping a chronic state of physical fragility and psychological stress.
Compounding this biologic susceptibility was the early death of his father during childhood, a psychologically disruptive event that forced the patient into a quasi-parental role for his two younger siblings. This premature social responsibility seemed to consolidate cognitive patterns of excessive self-sacrifice and over-responsibility, themes that later permeated his psychotic delusions during manic episodes.
In an effort to reduce infection frequency, the patient received repeated plasma-derived immunoglobulin infusions prior to modern viral screening protocols, leading to iatrogenic hepatitis C virus (HCV) infection, confirmed serologically at age 23. Following diagnosis, he began interferon-alpha monotherapy, which within weeks precipitated his first fully syndromic manic episode with psychotic features. Symptoms included expansive mood, grandiosity of delusional proportions, decreased need for sleep, pressured speech, and intrusive goal-directed behavior. Psychotic elements centered on messianic delusions, particularly the belief that he was chosen to “heal the world” through unrealistic philanthropic schemes. Hospitalization was required, and psychiatric stabilization was achieved after discontinuation of interferon-alpha and initiation of atypical antipsychotic therapy.
Over the following decades, the patient experienced three additional manic episodes, all displaying a stereotyped clinical profile: expansive or irritable mood, delusional grandiosity, drastically reduced sleep, circumstantial speech, distractibility, and disinhibited risk-taking behaviors. Psychotic content remained remarkably consistent, revolving around elaborate global-redeemer or political-visionary delusions.
Between episodes, partial functional recovery was observed, although persistent subsyndromal mood symptoms impaired his occupational and interpersonal life. Limited insight, especially during prodromal phases, often led to delayed treatment engagement and recurrent hospital admissions prompted by third-party intervention.
At age 33, during his second manic episode, the patient sustained a severe traumatic brain injury (TBI) following a high-speed car accident, under the influence of delusional beliefs about physical invulnerability. Neuroimaging confirmed right frontotemporal contusions. Post-injury neuropsychological evaluations revealed mild executive dysfunction, but the phenomenology of subsequent manic episodes remained consistent with primary BD-I rather than secondary organic mood disorder.
At discharge following his fourth hospitalization, the patient was prescribed olanzapine and, for the first time, valproate was introduced as a mood stabilizer.
DiscussionThis case offers a compelling illustration of how biological vulnerability, psychosocial adversity, and immune-inflammatory pathways may converge in the pathophysiology and course of BD-I.5,6 The early death of his father introduced a profound psychosocial stressor during a critical neurodevelopmental window.7 Early bereavement is known to disrupt attachment systems and alter Hypothalamic–Pituitary–Adrenal (HPA) axis function, lowering emotional resilience and increasing susceptibility to mood disorders later in life.6–8
Adding to this was the patient's SIgAD, a condition associated with immune dysregulation, heightened inflammatory tone, and susceptibility to autoimmunity.9 Chronic infections and immune dysregulation in SIgAD likely generated sustained systemic inflammatory states, which, according to emerging models of mood disorder pathogenesis, can lower the excitability threshold of cortico-limbic circuits and contribute to the onset of psychiatric symptoms.9,10
The iatrogenic acquisition of HCV and subsequent interferon-alpha treatment appear to have acted as a biological catalyst, unmasking an underlying affective diathesis. Interferon-alpha, known for its potent immune-activating and proinflammatory properties, has been repeatedly implicated in the induction of mood disorders, particularly mania and depression, via mechanisms involving cytokine-induced neurotoxicity, serotonin metabolism alteration, and HPA axis dysregulation.11–13
Of particular interest is the patient's clinical trajectory, which lends itself to interpretation through the lens of the kindling hypothesis.14 First formulated in epilepsy research, kindling refers to the phenomenon whereby repeated subthreshold stimulation results in increased neural excitability and lower thresholds for subsequent episodes.15–17 Applied to affective disorders, this model proposes that each manic episode may sensitize neural networks, particularly those involving frontolimbic circuits, progressively reducing the need for external triggers and fostering autonomous episode recurrence.6 The patient's early episodes were temporally linked to identifiable immunological and psychosocial stressors, while later episodes occurred in the absence of clear external provocations, in line with this progressive sensitization model.6
The TBI sustained during his second manic episode added further neurobiological complexity. Although subsequent episodes retained their primary affective character, brain trauma involving frontotemporal regions, key substrates for mood regulation and cognitive control, likely compounded his vulnerability, subtly shaping his clinical course.18
In conclusion, this case exemplifies how early life stress, immune dysfunction, neuroinflammation, and neural sensitization may converge in the emergence and perpetuation of bipolar disorder. It also reinforces the necessity of adopting a neuroprogressive framework when conceptualizing mood disorders, particularly in medically complex patients. Clinicians must remain vigilant to the role of immune modulation as a potential risk factor for mood destabilization, and embrace integrative treatment models that consider both biological and psychosocial dimensions of vulnerability.
Author contributionsDra. Alemañ Prats was responsible for identifying and selecting the clinical case, conducting a detailed review of the patient's medical history. In addition, she contacted the patient to obtain informed consent and coordinated the collection of the clinical data necessary for the study. All authors performed a literature review to contextualize the case within current research. Dra. García-Fernández contributed to drafting the initial manuscript, providing her expertise in interpreting the medical history and in the discussion section. Additionally, she participated in the critical review of the content, ensuring the clarity and scientific rigor of the article. All authors have approved the final version of the manuscript and affirm that the content accurately reflects the data obtained, complying with the required ethical and scientific standards.
Ethical considerationsAll protocols for publishing patient data were adhered to, ensuring patient privacy, and consent for publication was obtained from the patient.
FundingThis article was prepared without any funding support.
The authors declare no conflicts of interest.