Double burden of cancer and bipolar disorder: Implications for mental health care

Abstract

The coexistence of cancer and bipolar disorder (BD) represents a clinically relevant yet underexplored challenge at the intersection of psychiatry and oncology. Patients with BD may face increased vulnerability during cancer care due to biological, pharmacological, and psychosocial factors. At the same time, cancer and its treatments may destabilize mood and complicate psychiatric management. This narrative review synthesizes current evidence on the bidirectional relationship between BD and cancer. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science for articles published between 2000 and 2026 using combinations of the terms “bipolar disorder”, “cancer”, “neoplasms”, “inflammation”, “HPA axis”, “drug interactions”, and “psycho-oncology”. Population-based studies, clinical cohorts, systematic reviews, and mechanistic studies were prioritized to examine epidemiological associations, shared biological pathways, treatment-related psychiatric complications, and pharmacological interactions. Available evidence suggests that the relationship between BD and cancer is multifactorial and bidirectional. Patients with BD may experience higher cancer burden and poorer oncological trajectories due to lifestyle factors, healthcare disparities, and systemic biological vulnerabilities including chronic inflammation, neuroendocrine dysregulation, and oxidative stress. Conversely, cancer-related inflammation, corticosteroid exposure, chemotherapy, and immunotherapy may precipitate mood destabilization. Psychotropic-oncologic drug interactions further complicate treatment management. Emerging evidence also highlights the potential role of intracellular stress signaling and immune-related pathways linking psychiatric and oncologic processes. The intersection of BD and cancer represents a “double burden” shaped by biological, clinical, and psychosocial mechanisms. Improved collaboration between psychiatry and oncology, early psychiatric screening in cancer care, and careful pharmacological monitoring are essential to optimize outcomes in this vulnerable population.

Key Words: Cancer; Bipolar disorder; Inflammation; Psychological factors; Mental health; Psycho-oncology

Core Tip: Patients with bipolar disorder represent a clinically vulnerable population in oncology, facing increased cancer risk, delayed diagnosis, and a high likelihood of mood destabilization during cancer treatment. This review highlights how shared inflammatory and neuroendocrine pathways, together with corticosteroid exposure and complex drug-drug interactions, may worsen both psychiatric and oncological outcomes. Recognizing bipolar disorder as a relevant modifier of cancer care is essential to promote early screening, individualized pharmacological strategies, and integrated psychiatry-oncology collaboration aimed at improving survival and quality of life.

INTRODUCTION

Bipolar disorder (BD) is a recurrent, chronic and severe mood disorder which manifests as an alternation between episodes of mania, hypomania and depression. It affects at least 2% of the world population[1,2]. Patients with BD, as other patients with severe mental illness (SMI), show an increased mortality risk linked to numerous avoidable diseases[3]. BD is in fact a systemic condition associated with a high burden of medical comorbidities and most of the excess premature mortality in BD patients is not linked to psychiatric causes (e.g. suicide), it is rather due to medical comorbidities such as cardiovascular diseases or cancer[4-6]. BD occurs earlier in life of these patients and may increase the risk of developing these comorbidities and their outcomes.

In recent years, growing attention has been directed toward the potential association between BD and cancer. The latter remains one of the leading causes of morbidity and mortality globally, and its interaction with SMI such as BD is a major public health concern[7,8]. Large population-based studies report that patients affected by BD have a higher overall cancer incidence regarding oral, esophageal, breast, respiratory, skin and ovarian cancer[4,9-12]. Most of these data, especially those for breast cancer, were confirmed by a recent meta-analysis[13]. It is important to note that epidemiological findings regarding cancer risk in BD are not entirely consistent. While some population-based studies suggest increased incidence or poorer oncologic outcomes, other studies report comparable or even lower cancer rates in certain cohorts. These inconsistencies may reflect methodological differences, lifestyle confounders, variations in healthcare access, and heterogeneity in BD subtypes and treatment exposure.

At the biological level several pathophysiological mechanisms can potentially link BD with cancer. These include low-grade inflammation[4,9,11] and immune dysregulation[14-18], oxidative stress[19], hypothalamic-pituitary-adrenal (HPA) axis dysregulation[20,21], genetic susceptibility[22] and the use of BD treating medications that can interfere with carcinogenesis, especially in breast cancer and other estrogen-dependent tumors[23,24].

Other important factors that lead to bigger risk of cancer and worsen the outcomes are lifestyle factors such as substance use, stigma, insufficient access to preventative care and isolation and fragmentation of health services[25].

Emerging data suggest that cancer-related inflammatory processes, corticosteroid exposure, chemotherapy, and newer immunotherapies can precipitate mood destabilization, mixed affective states, delirium, and cognitive impairment, particularly in patients with pre-existing mood disorders[26-28]. To provide an overview of the complex and bidirectional relationship between BD and cancer, the principal shared biological, clinical, and psychosocial mechanisms are summarized in Figure 1.

Figure 1 Conceptual framework of the bidirectional relationship between bipolar disorder and cancer. HPA: Hypothalamic-pituitary-adrenal; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor alpha.

Moreover, the management of BD during oncological treatment is complicated by potential drug-drug interactions (DDIs), altered pharmacokinetics (PKs), and the need to balance mood stabilization with cancer-related toxicity[29].

The aim of this narrative review is to provide a BD-specific synthesis of the cancer-psychiatry interface by integrating epidemiological findings, shared biological and neuroendocrine mechanisms, treatment-related psychiatric complications, pharmacological interaction risks, and psychosocial determinants across the cancer care trajectory. Unlike broader psycho-oncology reviews focused on SMI as a heterogeneous category, the present review specifically examines BD as a clinically distinct condition characterized by recurrent mood instability, systemic inflammatory burden, and complex psychopharmacological management. We propose a bidirectional clinical-translational framework in which BD may influence cancer risk and care trajectories, cancer and its treatments may destabilize mood, and shared biological vulnerabilities may contribute to adverse outcomes in both domains.

METHODOLOGY

This article was conducted as a narrative review aimed at synthesizing the available literature on the bidirectional relationship between BD and cancer, with a focus on epidemiological evidence, shared biological mechanisms, treatment-related psychiatric complications, pharmacological interactions, and psychosocial determinants. A literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science for articles published from January 2000 to January 2026. Search terms included combinations of “bipolar disorder”, “mania”, “hypomania”, “cancer”, “neoplasms”, “oncology”, “inflammation”, “HPA axis”, “corticosteroids”, “drug-drug interactions”, “lithium”, and “psycho-oncology”. We prioritized systematic reviews, meta-analyses, population-based studies, longitudinal cohort studies, and clinically relevant translational papers; selected case reports and case series were included when they addressed specific issues of direct clinical importance, such as lithium monitoring during chemotherapy or corticosteroid-induced mania. We included English-language publications involving adult populations or mechanistic/translational evidence relevant to BD and oncology. We excluded papers focused exclusively on other SMIs without extractable BD-specific implications, pediatric-only studies, and articles lacking sufficient relevance to the clinical or biological scope of the review. Because the aim was interpretive and integrative rather than exhaustive, the findings were synthesized narratively and organized into epidemiological, mechanistic, pharmacological, and psychosocial domains.

CANCER INCIDENCE AND RISK IN BD: EPIDEMIOLOGICAL EVIDENCE

Epidemiology data about the overall incidence of cancer among individuals with BD have yielded heterogeneous results. An inpatient cohort study from Israel reported a significantly elevated overall cancer incidence in BD for both men [standardized incidence ratio (SIR) = 1.59, 95%CI: 1.01-2.17] and women (SIR = 1.75, 95%CI: 1.31-2.18), with a non-significant increase in breast cancer risk (SIR = 1.70, 95%CI: 0.99-2.41)[9]. A nationwide Taiwanese cohort study of individuals admitted for affective disorders found a higher cancer incidence in patients with BD compared to the general population (incidence 4.22 per 1000 person-years in BD vs 3.03 per 1000 person-years in the general population) with an elevated SIR for BD (SIR = 1.39, 95%CI: 1.26-1.53). Cancer sites that were majorly related to both tobacco and alcohol use (buccal cavity, oesophagus, larynx and liver) had the higher incident rates compared to cancer sites that were related to either tobacco (lung, nasal cavity, paranasal sinuses, pancreas, stomach, kidney, bladder, uterine cervix and myeloid leukemia) or alcohol (colorectal and breast) use or cancer sites that were less related to either of these substances (skin cancer, brain tumour, thyroid cancer)[11]. Another Taiwanese study found similar results (SIR = 1.29, 95%CI: 1.11-1.51)[12]. A recent Taiwanese nationwide population-based study found that patients with BD, and their unaffected relatives, have an overall elevated cancer risk [odds ratio (OR) = 1.22, 95%CI: 1.06-1.40], data were especially significant for skin (OR = 2.70, 95%CI: 1.10-6.63) breast (female only OR = 1.98, 95%CI: 1.39-2.51) and ovary (OR = 2.82, 95%CI: 1.43-5.53) cancer, compared to individual without severe mental disorders. A large United Kingdom primary care study found that patients with BD had a greater risk of developing respiratory cancer compared to the general population, nevertheless, the result was considered nonsignificant after adjusting the data taking into account smoking and comorbidities. The same study found that cancer risk for other types of cancer (such as gastroesophageal, prostate, colorectal and breast cancer) in people with BD was similar to the general population after adjustment[10].

INFLAMMATION AS A CONVERGENT MECHANISM IN BD AND CANCER

Inflammation has been recently considered as a core pathophysiological mechanism in BD, interacting with neurotransmitter regulation, neural circuitry, neuroplasticity and metabolism[30,31]. Peripheral inflammation, characterised by the rising of circulating cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 has been observed in several studies both in acute manic and depressive episodes[32-34]. Among these inflammatory markers TNF-α seems to be the key player. The blood levels of this cytokine have been consistently reported as increased in patients with BD during acute mood episodes including in the early phases of the affective disorder[35,36]. IL-6 shows both state and trait related elevations and it correlates with symptom severity (including higher scores on the Young Mania Rating Scale) and cognitive dysfunction[37-39]. Elevated levels of interferon-gamma (IFN-γ) have also been reported in patients with BD[40], however meta-analysis failed to detect significant differences between individual with BD and controls[41]. Regardless there is some indirect evidence of the role of IFN-γ. Therapies with IFN-α or beta tend to worsen or even trigger depressive and manic symptoms proving the contribution of IFN in mood regulation also regarding its role in the control of the HPA axis[42,43]. Low-grade systemic inflammation is further reflected by elevated C-reactive protein during acute bipolar episodes, with partial normalisation during euthymia and greater elevations than in unipolar depression[15]. Anti-inflammatory cytokines such as IL-4 and IL-10 show phase-dependent and stage-dependent alterations, suggesting dysregulated compensatory mechanisms over the course of illness. IL-10 production tends to decline in more advanced stage of the disorder[44,45].

Evidence indicates that cancer is associated with systemic dysregulation of cytokine networks, with concurrent upregulation of pro-inflammatory and immunosuppressive mediators. A meta-analysis shows that patients with malignant tumors exhibit elevated circulating levels of cytokines such as TNF-α, IL-6, IL-10 and macrophage inhibitory factor, reflecting a state of chronic inflammation accompanied by impaired antitumor immune surveillance. In particular, increased IL-6 and TNF-α, also shown in patients with BD in acute episodes, have been associated with suppression of key immune pathways, including the IL-12/IFN-γ axis and reduced human leukocyte antigen-DR expression, suggesting that systemic cytokine alterations contribute to immune dysfunction even beyond the tumor microenvironment[46]. A recent meta-analysis focusing on breast cancer described a worse overall survival and poorer treatment response, supporting their role as adverse prognostic biomarkers. However, the heterogeneity in study design and cytokine cut-off values currently limits their translation into routine clinical practice[47].

Regarding other affective disorders such as anxiety and depression there is evidence about the role pro-inflammatory cytokines and chemokines, in particular TNF-α, IL-6, IL-1, CXC8/IL-8 which promote angiogenesis, tumor cell proliferation, resistance to apoptosis and genomic instability through the production of reactive oxygen and nitrogen species. These mediators activate key signalling pathways, including nuclear factor kappa B and signal transducer and activator of transcription 3, sustaining a self-perpetuating inflammatory loop that favours tumor cells survival and immune evasion[48]. The cytokine hypothesis of in mood disorders suggests that behavioural changes observed in cancer patients are caused by proinflammatory cytokines produce by tumor cells that affects the central nervous system function. Binding to receptors in nerve cells the cytokines can influence the metabolism of serotonin, the HPA axis and neural networks associated with mood disorders in the hippocampus and other limbic regions[49]. The strength of the current evidence remains heterogeneous. While inflammatory alterations have been consistently documented in BD and are well established in cancer biology, direct studies examining inflammatory mechanisms specifically in patients affected by both conditions are still limited.

At the state-of-the-art data shows that there might be an interplay between BD and cancer. The elevation of cytokines seen in both BD and cancer can lead to a worse outcome in both morbidities by favouring immune evasion of tumour cells and by triggering acute mood episodes in BD.

Intracellular stress signaling and tumor microenvironment pathways

Recent studies have further highlighted the potential role of intracellular stress signaling and immune-related pathways in linking psychiatric disorders with systemic diseases. For instance, alterations in endoplasmic reticulum-mitochondria communication have been reported in cellular models derived from patients with BD, suggesting that mitochondrial dysfunction and disrupted cellular stress responses may represent important biological features of the disorder[50]. At the systemic level, chronic psychological stress has been shown to influence neuroendocrine and inflammatory pathways, potentially affecting immune regulation and cellular homeostasis[51]. In oncology, increasing attention has been directed toward signaling pathways within the tumor microenvironment that regulate immune responses and tumor progression. Recent work has identified molecular regulators involved in immune modulation and tumor growth, further supporting the role of complex immune-inflammatory networks in cancer biology[52].

Although direct evidence linking these pathways specifically to BD-related cancer vulnerability remains limited, their convergence suggests that stress-sensitive biological systems may contribute to the observed overlap between psychiatric and oncologic processes.

Corticosteroid exposure and mood destabilization in oncology

Corticosteroids have been used in cancer therapy being particularly effective in treating brain metastases, bowel obstruction, superior vena cava syndrome and spinal cord compression. They are also used to stimulate appetite, control vomit and reduce tumor induced inflammation[53]. The use of corticosteroids is associated with neuropsychiatric side effects including affective, behavioural and cognitive manifestations[54]. The induction of manic, hypomanic or mixed episodes is one of the most common side effects linked to the use of corticosteroid therapy and it is also related to the duration of the therapy and the dosage used[55,56]. Patients with psychiatric disorders, such as BD, are especially susceptible to corticosteroid-induced psychiatric effects even when the disorder is previously well controlled, suggesting an underlying biological susceptibility[55,57,58].

HPA axis dysregulation in BD and cancer

Cortisol levels are controlled by the HPA axis that has a crucial function in responding to stressful external events but also to emotional internal stressors. Dysfunction of the stress axis has been described in patients with BD[21,59]. The activity of the HPA axis is regulated by the secretion of corticotropin-releasing hormone (CRH) and arginine-vasopressin by the hypothalamus, that stimulates the secretion of the adrenocorticotropic hormone by the pituitary gland that ultimately leads to the secretion of glucocorticoids by the adrenal gland[59]. There is evidence of innervation by catecholaminergic, serotonergic and dopaminergic neurons of the CRH-producing nerve cells in the hypothalamus, therefore influencing the release of CRH and the regulation of the whole axis[60]. The serotonergic system mediates most of the symptoms of bipolar patients such as impulsivity, aggressivity and mood disorders. Serotonergic neurons in the raphe nucleus are connected with the HPA axis, the amygdala and the hippocampus suggesting the core role of this system in the HPA axis dysregulation seen in patients with BD[59]. This pattern of alteration in the HPA axis is interestingly seen in patient who experienced early life stress, especially maltreatment, abuse and neglect, all causes that seems to lead to permanent pathophysiological dysfunctions similar to those observed in patients with BD[61]. Similar pattern of HPA axis dysregulation have been reported in patient with cancer, where systemic inflammation and psychological stress concur to disrupt circadian cortisol rhythms. In particular, oncological populations exhibit a flattened diurnal cortisol profile and elevated cortisol levels in the evening. This pattern is associated with fatigue, depressive symptoms, functional impairment and poorer survival outcomes[62-64]. These findings are common across cancer types as shown in a recent systematic review[20]. Another burden to the HPA axis regulation is of course the use of exogenous corticosteroids as we discussed in the precedent paragraph. The convergence of HPA axis abnormalities in BD and cancer suggest a shared vulnerability to stress-related neuroendocrine dysregulation. In patients affected by both conditions the double burden on the HPA axis may amplify stress sensitivity and contribute to adverse psychiatric and somatic outcomes.

The “double burden” should not be interpreted as proof of a direct causal pathway from BD to cancer or vice versa. Rather, current evidence supports a multifactorial model in which behavioral, healthcare-related, treatment-related, and biological factors interact dynamically, while many observed associations remain non-causal and potentially confounded.

Many available studies rely on cross-sectional designs and small clinical samples, which limits the possibility of establishing causal relationships between neuroendocrine dysregulation and cancer outcomes in bipolar populations.

PSYCHOSOCIAL FACTORS, STIGMA, AND INEQUALITIES IN CANCER CARE

The psychosocial impact of a cancer diagnosis in individuals with BD must be understood within the broader framework of SMI, as the available literature rarely isolates BD-specific oncological outcomes. From a social perspective, individuals with BD frequently experience reduced social support, stigma and socioeconomic disadvantage[65,66] and meta-analysis, regarding general cancer population, demonstrates that these psychosocial factors indirectly contribute to worse outcomes in the oncological population[67]. Poor health care in people with BD is often associated with the problem of stigma that profoundly affects patients’ psychosocial functioning and engagement in healthcare. Researche in psychiatric settings regarding people with SMI, including individuals with BD, indicates that the dimension of stigma encompasses both social stigma, as the series of stereotyped beliefs, prejudices and discriminatory attitudes, and self-stigma, as the internalization of a negative stereotype that the person applies to oneself[68]. Patients with SMI tend to undergo screening programmes and are more likely to have metastases at diagnosis[7,25], there are also data demonstrating higher cancer-related mortality among people with mental illness compared to the general population[69,70]. This may be linked to both the functional impairment of these patients, the difficulties of health care providers in relating to psychiatric patients and the fragmentation of health care services[7].

Cancer patients often necessitate structured psychosocial support throughout the care continuum. This is even more important in patients with a pre-existent psychiatric illness. For cancer patients, interventions may include psychoeducation, cognitive-behavioral approaches, mindfulness-based stress reduction, and supportive counseling, which aim to improve coping skills, reduce anxiety, enhance quality of life and maintain adherence to the treatment across different phases[71]. There is evidence that structured psychotherapeutic intervention, in particular those in the cognitive-behavioural framework, are the most effective modalities to reduce psychological symptoms and enhance adaptive functioning in cancer patients. Structured therapies such as cognitive behavioral therapy, acceptance and commitment therapy, and meaning-centered psychotherapy have demonstrated significant efficacy in alleviating depression, anxiety, and maladaptive thought patterns by helping patients identify negative cognitions, reframe illness-related beliefs, and cultivate meaning and psychological flexibility in the face of cancer-related stressors[72,73]. Caregiver-focused psychological interventions are increasingly recognized as a cornerstone in psychosocial intervention. This takes on even greater importance in BD and other psychiatric illnesses. A systematic review indicates that psychoeducational, emotion-focused, and problem-solving interventions can improve caregiver well-being, reduce depressive symptoms, and enhance resilience, particularly when delivered as dyadic or tailored support programs alongside patient care[74].

Beyond biological vulnerability, psychosocial determinants and healthcare system factors play a crucial role in shaping cancer outcomes among individuals with BD. Patients with BD frequently experience stigma, reduced access to preventive care, delayed diagnosis, and fragmented service delivery, all of which may contribute to poorer oncological prognosis. Table 1 summarizes key psychosocial and healthcare-related domains associated with adverse cancer outcomes in patients with SMI, highlighting the available evidence and their clinical implications, with particular relevance for individuals with BD.

Table 1 Psychosocial and healthcare-related factors affecting cancer outcomes in patients with bipolar disorder.

Domain	Key findings	Evidence	Impact on cancer outcomes	Clinical implications
Stigma	Severe mental illness patients less likely to receive screening	Observational studies	Delayed diagnosis, advanced stages	Need for proactive screening
Healthcare access	Reduced access to oncologic care	Population-based studies	Higher cancer mortality	Integrated care pathways
Diagnostic delay	Later-stage cancer diagnosis	Cohort studies	Poorer prognosis	Early referral strategies
Psychological distress	High rates of depression, anxiety	Clinical studies	Reduced treatment adherence	Routine psychiatric assessment
Psychosocial interventions	Cognitive behavioral therapy, supportive therapy effective	Randomized controlled trials in cancer populations	Improved quality of life and adherence	Adaptation for bipolar disorder needed
Care coordination	Multidisciplinary models beneficial	Integrated care studies	Improved continuity of care	Psychiatry-oncology collaboration

It provides an overview of major psychosocial and healthcare-related domains influencing cancer outcomes in patients with bipolar disorder and other severe mental illnesses. For each domain, key findings, type of supporting evidence, impact on cancer outcomes, and potential clinical implications are summarized. It emphasizes how stigma, reduced healthcare access, diagnostic delays, psychological distress, and inadequate care coordination can negatively affect cancer prognosis and treatment adherence, underscoring the need for proactive screening strategies and integrated psychiatry-oncology care models.

LITHIUM: POTENTIAL ANTICANCER EFFECTS AND CLINICAL CONSIDERATIONS IN ONCOLOGY

Lithium is a cornerstone in acute and maintenance treatment for BD. Growing interest has emerged for its potential role in cancer treatment. The neuroprotective activity of lithium is connected to the inhibition of its molecular targets: (1) Inositol-monophosphate; (2) Glycogen-synthase-kinase 3β; and (3) Protein kinase C. Those targets are notably deregulated in cancer[75]. Lithium is transported across the cell membrane by the monocarboxylate transporters which are also used to transport lactate, pyruvate, D-β-hydroxybutyrate and acetoacetate[76]. These substrates are used by cancer cells to fuel lactic fermentation[77]. This raises the question whether lithium can have a role in deregulating cancer cells’ metabolism[75].

Lithium inhibits glycogen-synthase-kinase 3β, leading to growth arrest or apoptosis and indirectly targeting the Wnt metabolic pathway, nuclear factor kappa B-dependent gene transcription and rat-1[78]. Studies on the role of lithium in the apoptotic process show contradictory results. In HepG2 cells and malignant glioma cell lines it shows a non-proapoptotic effect[79,80] while its proapoptotic properties have been demonstrated in multiple myeloma, human breast and colorectal cell lines, medullary thyroid cancer, human prostate cancer[81-83] and pancreatic ductal adenocarcinoma cells[84-86]. The rat-1 induced growth arrest leads to reduced cell growth and adenosine triphosphate concentration[87] in colon and breast cancer.

LiCl also shows promising results in treating conditions associated with cancer such as inflammation-mediated skeletal muscle wasting allowing to have better clinical outcomes in muscle atrophy and cancer cachexia[88]. Lithium has a role in reducing inflammation by inducing the production of IL-10 and reducing TNF-α[75].

Complementing these findings, epidemiologic studies in BD populations suggest a connection between lithium exposure and reduced cancer risk[89,90].

However current evidence does not support lithium as an anticancer therapy outside research settings at the state of the art. In patients with BD undergoing cancer treatment the use of lithium requires a proactive coordination with oncology because of its narrow therapeutic index and the higher likelihood of dehydration, renal function fluctuation and drug interactions during cancer care. Lithium is primarily eliminated by the kidney, making its exposure highly sensitive to changes in glomerular filtration and tubular handling. In oncology, this is clinically relevant because several antineoplastic agents, and the supportive-care context surrounding chemotherapy, can acutely alter renal function, hydration status, and electrolyte balance. The best-documented interaction involves cisplatin-based chemotherapy, where case reports/series measuring lithium in serum and urine describe substantial fluctuations in lithium concentrations during treatment courses, consistent with a renal interaction and the well-known nephrotoxic potential of cisplatin[91-94]. These observations support a practical approach in which lithium can sometimes be continued, but only with close monitoring of lithium levels and renal function around each chemotherapy cycle, and with proactive management of dehydration, vomiting/diarrhea, and nephrotoxic co-medications. Beyond platinum agents, older clinical data raised safety signals in specific settings: In a cohort of cancer patients receiving combination chemotherapy including an anthracycline, lithium administration in those with pre-existing cardiovascular abnormalities was associated with a higher risk of sudden death, suggesting that cardiac vulnerability and treatment context may modify risk[95].

PK AND PHARMACODYNAMIC DDIs IN ONCOLOGY AND BD

An important challenge in treating cancer in BD patients are DDIs. Polypharmacy is often unavoidable but antipsychotics and mood stabilizers have important PK and pharmacodynamic (PD) interactions with oncologic agents influencing both therapeutic efficacy and toxicity.

PK interactions between psychotropics and anticancer agents

Mood stabilizers such as carbamazepine are considered strong inducers of some cytochromes (CYP) of the hepatic P450 system. Carbamazepine interacts with CYP 3A4 inducing its activity, and reducing plasma concentration of those drugs metabolized by this CYP. The concomitant treatment with carbamazepine reduces plasma concentration of vinca alkaloids (vinblastine, vincristine and vindesine), taxanes (both paclitaxel and docetaxel), etoposide, teniposide and methotrexate[96]. Conversely valproic acid is considered an inhibitor of certain metabolic pathways, leading to increasing toxicity of agents like etoposide and nitrosoureas[96].

Antipsychotic medications undergo extensive hepatic metabolism and are substrate for multiple CYP enzymes and co-administration with cancer therapies that induce or inhibit these enzymes can significantly alter plasma concentrations, therapeutic efficacy and toxicity profiles of both antipsychotics and anticancer drugs. Second-generation antipsychotics exhibit distinct dependence on CYP isoforms[97]. Clozapine is primarily metabolized by CYP1A2 with contributions from CYP2D6, CYP2C19, and CYP3A4; risperidone is metabolized mainly by CYP2D6 and to a lesser extent CYP3A4; olanzapine is detoxified principally via CYP1A2 as well as through glucuronidation; quetiapine and ziprasidone rely heavily on CYP3A4 for biotransformation; and aripiprazole and paliperidone involve CYP2D6 and CYP3A4 pathways[98]. These differential metabolic pathways underscore how oncologic agents that modulate CYP activity can impact antipsychotic exposure. For instance, tyrosine kinase inhibitors or certain hormonal therapies frequently used in cancer treatment can act as CYP3A4 inducers or inhibitors, diminishing or elevating plasma levels of quetiapine, ziprasidone, or aripiprazole. Similarly, CYP1A2 inducers, such as defactinib, may accelerate the clearance of clozapine and olanzapine, potentially reducing their effectiveness and necessitating dose adjustments[97].

In addition to psychosocial determinants, BD and cancer share multiple biological and treatment-related mechanisms that may contribute to their bidirectional interaction. These mechanisms involve immune-inflammatory activation, neuroendocrine dysregulation, genetic vulnerability, and the effects of psychotropic and oncological treatments. Table 2 summarizes the principal shared biological pathways between BD and cancer, integrating available evidence from both fields and outlining their potential clinical implications.

Table 2 Shared biological and treatment-related mechanisms linking bipolar disorder and cancer.

Domain	Mechanism	Evidence in BD	Evidence in cancer	Clinical implications
Inflammation	Tumor necrosis factor alpha, interleukin-6 have increased	Acute episodes, early BD	Tumor progression, immune evasion	Mood destabilization, worse prognosis
Hypothalamic-pituitary-adrenal axis	Cortisol dysregulation	Flattened rhythm	Reduced survival	Stress vulnerability
Corticosteroids	Exogenous glucocorticoids	Mania induction	Supportive cancer care	High psychiatric risk
Genetics	Shared single nucleotide polymorphisms	Immune-related genes	Cancer susceptibility	Biological vulnerability
Lithium	Glycogen-synthase-kinase 3β inhibition	Mood stabilization	Anti-proliferative effects (preclinical)	Requires strict monitoring
Drug interactions	Cytochrome P450 modulation	Pharmacokinetic/pharmacodynamic alterations	Chemotherapy toxicity	Need interdisciplinary care

It summarizes the main biological and treatment-related domains that converge in bipolar disorder and cancer. For each domain, the underlying mechanism, evidence in bipolar disorder, evidence in cancer, and key clinical implications are reported. It highlights how chronic inflammation, hypothalamic-pituitary-adrenal axis dysregulation, corticosteroid exposure, shared genetic susceptibility, lithium-related molecular pathways, and pharmacokinetic and pharmacodynamic drug-drug interactions may jointly contribute to mood destabilization and adverse oncological outcomes, underscoring the need for interdisciplinary clinical management. BD: Bipolar disorder.

PD interactions: Cardiac safety and sedation, and hematologic risk

Beyond PK mechanisms, PD interactions play a critical role in the safety and tolerability of concomitant psychotropic and oncologic therapies. A particularly important category of PD interaction concerns cardiac electrophysiology, especially QT interval prolongation. Many oncological drugs such as tamoxifen, platinum compounds and tyrosine kinase inhibitors are involved in QTc prolongation[99], thereby the concurrent use of antipsychotic medications that lengthen QT interval increase the risk of additive QT prolongation and consequential ventricular arrhythmias such as torsade de pointes[100].

Sedation is one of the most common side effects when using mood stabilizers or antipsychotic medications. This sedation burden can be increased by the use of chemotherapeutic agents that commonly causse fatigue in oncological patients[101,102]. Hematologic toxicity is another important PD consideration. Some psychotropic agents, particularly clozapine, carry a risk of neutropenia or agranulocytosis, which may overlap with chemotherapy-induced myelosuppression. In such cases, careful coordination between oncology and psychiatry teams is essential to monitor blood counts and to balance psychiatric stability with oncologic safety.

Clinical management considerations in patients with BD receiving cancer therapy

The management of patients with BD undergoing cancer treatment requires close coordination between psychiatry and oncology. Early psychiatric assessment at the time of cancer diagnosis may help identify individuals at higher risk of mood destabilization during oncologic treatment[103].

Corticosteroids, frequently used in oncology, are well known to precipitate mood symptoms including insomnia, irritability, hypomania, or frank mania. Monitoring for early signs of affective activation is therefore recommended in patients with BD receiving steroid-based regimens.

For patients treated with lithium, clinicians should consider regular monitoring of serum lithium levels and renal function, especially during chemotherapy cycles associated with dehydration, vomiting, or nephrotoxic agents. When antipsychotics are prescribed, clinicians should also consider cardiac monitoring when combined with QT-prolonging oncologic drugs[104].

In clinical practice, patients with BD entering cancer care should undergo an early psychiatric and psychosocial assessment including current mood state, history of manic/mixed episodes, prior corticosteroid sensitivity, substance use, sleep disruption, adherence risk, and current psychotropic treatment. Baseline laboratory and safety assessment should include renal and thyroid function in patients receiving lithium, metabolic and electrocardiogram monitoring when antipsychotics are prescribed, and a structured review of potential DDIs before starting chemotherapy, endocrine therapy, or targeted agents. During cancer treatment, clinicians should actively monitor for new-onset insomnia, irritability, psychomotor activation, disinhibition, affective lability, depressive worsening, and delirium-like presentations, particularly after corticosteroid exposure or major treatment changes. Referral to psychiatry should be considered early when there is a prior history of BD I, mixed states, rapid cycling, poor adherence, or emergent mood destabilization. A stepped collaborative-care model may help match intervention intensity to psychiatric risk over time.

A collaborative care pathway involving oncology, psychiatry, primary care, pharmacy, and psycho-oncology may reduce fragmentation and improve both safety and treatment continuity.

Clinicians managing patients with BD during cancer treatment must consider potential drug-drug interactions between psychotropic medications and oncologic therapies. These interactions may involve both PK and PD mechanisms and may significantly affect treatment safety. Key clinically relevant interactions and monitoring recommendations are summarized in Table 3.

Table 3 Key psychotropic-oncologic drug interactions and monitoring recommendations.

Psychotropic drug/class	Relevant oncologic context	Potential interaction or risk	Monitoring/management recommendation
Lithium	Platinum-based chemotherapy, dehydration from chemotherapy (vomiting, diarrhea)	Reduced renal clearance leading to lithium toxicity	Monitor serum lithium levels, renal function, and electrolytes during treatment cycles
Carbamazepine	Taxanes, vinca alkaloids, etoposide	Cytochrome P450 enzyme system (CYP3A4) induction may reduce plasma levels of chemotherapeutic agents	Consider alternative mood stabilizer or monitor oncologic drug efficacy
Valproate	Hepatically metabolized anticancer drugs	Altered hepatic metabolism and potential hematologic toxicity	Monitor liver function tests and blood counts
Antipsychotics (e.g., quetiapine, haloperidol)	QT-prolonging anticancer agents	Additive QT interval prolongation and arrhythmia risk	Baseline and follow-up electrocardiogram monitoring
Clozapine	Myelosuppressive chemotherapy	Additive risk of neutropenia/agranulocytosis	Frequent blood count monitoring and close psychiatry-oncology coordination
Corticosteroids (oncologic supportive therapy)	Steroid-containing chemotherapy regimens	Risk of steroid-induced mania or mood destabilization	Monitor for insomnia, irritability, and manic symptoms; adjust mood stabilizer if needed

DISCUSSION

This narrative review highlights the complex and bidirectional relationship between BD and cancer, emphasizing epidemiological evidence, shared biological mechanisms, major clinical implications and concurrent psychosocial factors. Overall, available data suggest that individuals with BD experience an increased burden of cancer incidence and poorer oncological outcomes, although results remain heterogeneous across studies and cancer sites. There is also a literature gap about this important topic, since existing research examines patients with SMI as a homogeneous group including patients with BD, schizophrenia and major disorder in a single umbrella term. This approach is useful for public health analyses but limits the ability to investigate disorder-specific risk profiles and obscures important biological differences among these psychiatric conditions.

Population-based studies consistently report a higher overall cancer risk in individuals with BD, particularly for malignancies associated with tobacco and alcohol exposure, such as oral, esophageal, liver, and respiratory cancers[9,11,12]. These findings support the role of lifestyle factors and medical comorbidities, which are highly prevalent in BD, in mediating cancer risk. In contrast, large primary care studies that adjusted for smoking, obesity, and comorbid conditions found attenuated or non-significant associations between BD and several cancer types, including breast and colorectal cancer[10]. This discrepancy suggests that the excess cancer risk observed in BD may be partially explained by modifiable risk factors and inequalities in access to preventive healthcare rather than by the psychiatric disorder alone. Psychosocial factors and stigma play a critical role in shaping cancer outcomes in BD. Individuals with SMI are less likely to participate in screening programs and are more frequently diagnosed at advanced stages, contributing to increased cancer-related mortality[69,70]. Structured psychosocial interventions have demonstrated efficacy in improving psychological well-being and treatment adherence in cancer patients and may be particularly relevant for individuals with BD, although disorder-specific evidence remains limited.

However, emerging genetic and biological evidence challenges a purely behavioral explanation. Recent studies indicate shared genetic susceptibility between BD and cancer, including overlapping single nucleotide polymorphisms (SNPs). Two SNPS associated with BD (rs11144407 and rs4236274) were also responsible for an increased breast cancer risk[22] while rs6532496, an SNP involved in BD, was strongly related to an increased overall cancer risk[105]. These findings support a vulnerability model in which BD and cancer may share common biological pathways, contributing to their co-occurrence independently of lifestyle factors.

Chronic low-grade inflammation represents a central pathophysiological mechanism linking BD and cancer. Elevated circulating levels of pro-inflammatory cytokines, particularly TNF-α and IL-6, are consistently reported in acute mood episodes and early stages of BD and have been implicated in tumor progression, angiogenesis, and immune evasion[32,46]. The convergence of inflammatory profiles in BD and cancer may contribute to poorer outcomes in both conditions, promoting mood destabilization in BD and impairing antitumor immune surveillance in oncology.

Neuroendocrine dysregulation further strengthens this link. Alterations of the HPA axis are well documented in BD and are similarly observed in cancer populations, where flattened diurnal cortisol rhythms and elevated evening cortisol levels are associated with fatigue, depressive symptoms, and reduced survival[20,21]. In patients affected by both conditions, the cumulative burden on the stress-response system may amplify vulnerability to adverse psychiatric and somatic outcomes.

Cancer treatments represent an additional destabilizing factor. Corticosteroids, widely used in oncological settings, are a well-established trigger of manic, hypomanic, and mixed affective episodes, particularly in individuals with BD[54,56].

From a pharmacological perspective, the management of BD during cancer treatment is challenged by clinically relevant drug-drug interactions. Mood stabilizers and antipsychotics frequently interact with antineoplastic agents via cytochrome P450 pathways, altering drug exposure and increasing the risk of toxicity[96,97]. PD interactions, including QTc prolongation and additive sedation, further increase clinical risk and underscore the need for careful monitoring and interdisciplinary collaboration[99,102].

Lithium deserves particular attention. Although preclinical and epidemiological data suggest potential anticancer and anti-inflammatory effects, current evidence does not support its use as an oncological treatment. In patients with BD undergoing cancer therapy, lithium administration requires strict monitoring due to its narrow therapeutic index and susceptibility to renal impairment, dehydration, and interactions with nephrotoxic agents such as platinum-based chemotherapy[91,92,94].

Taken together, the evidence supports a three-level framework for understanding the cancer-BD interface. First, BD may act as a modifier of cancer risk and cancer care through behavioral risk factors, comorbidity burden, stigma, and reduced access to preventive services. Second, cancer and its treatments may destabilize bipolar illness through inflammatory activation, corticosteroid exposure, circadian disruption, metabolic stress, and pharmacological interactions. Third, both conditions appear to converge on partially overlapping biological pathways, including chronic inflammation, HPA axis dysregulation, oxidative stress, mitochondrial dysfunction, and immune-related signaling. This framework may help clinicians avoid simplistic causal interpretations and instead conceptualize the relationship as bidirectional, multifactorial, and clinically dynamic.

This review has several limitations. Its narrative design does not allow the methodological exhaustiveness or formal risk-of-bias assessment typical of systematic reviews. The available literature is highly heterogeneous with respect to populations, cancer types, illness phase, psychotropic exposure, and outcome definitions. A substantial proportion of the evidence derives from studies on SMI more broadly, rather than BD-specific oncology cohorts, which limits diagnostic precision. Many mechanistic links remain inferential and are supported by parallel evidence from psychiatry and oncology rather than direct studies of patients affected by both conditions. Finally, residual confounding by smoking, alcohol use, obesity, socioeconomic disadvantage, healthcare access, and treatment exposure complicates causal interpretation of epidemiological associations.

CONCLUSION

The available evidence indicates that BD and cancer are linked through a complex interplay of biological vulnerability, lifestyle factors, treatment-related effects, and healthcare inequalities. Chronic inflammation, HPA axis dysregulation, and shared genetic pathways may contribute to the bidirectional relationship between these conditions, while cancer treatments and psychotropic medications introduce additional clinical challenges.

The interaction between BD and cancer is best understood as the result of converging biological vulnerabilities and treatment-related factors, rather than as a unidirectional association. Chronic inflammation, HPA axis dysregulation, exposure to corticosteroids, pharmacological interactions, and shared genetic susceptibility may synergistically increase the risk of mood destabilization and poorer oncological outcomes.

All these findings highlight the importance of integrated, multidisciplinary care models involving psychiatry, oncology, and primary care. Early cancer screening, proactive management of mood symptoms, careful monitoring of pharmacological interactions, and access to tailored psychosocial support are essential to improving outcomes in this vulnerable population.

Despite growing recognition of the complex interaction between BD and cancer, important knowledge gaps remain. First of all, there is a clear need for longitudinal studies examining psychiatric trajectories across the cancer care continuum in individuals with BD. Most existing evidence derives from cross-sectional or retrospective studies, which limits the ability to clarify temporal relationships between cancer diagnosis, treatment exposure, and mood destabilization. Prospective cohorts following patients from cancer diagnosis through active treatment and survivorship would help identify critical periods of psychiatric vulnerability and guide preventive interventions.

Besides, further biomarker-based research is needed to clarify the biological mechanisms linking BD and oncological outcomes. In particular, studies integrating inflammatory markers, neuroendocrine measures, mitochondrial and intracellular stress signaling pathways, and immune-related mechanisms may help identify shared pathophysiological processes contributing to both psychiatric instability and cancer progression. Such approaches may also enable the identification of biological signatures associated with higher vulnerability to mood destabilization during oncologic treatment.

Future work should also focus on the development and evaluation of integrated psycho-oncology care models tailored to patients with BD. Given the complexity of pharmacological management and the potential for treatment-related psychiatric complications, collaborative care pathways involving oncologists, psychiatrists, psycho-oncology specialists, and clinical pharmacists may be particularly beneficial. Evaluating the impact of these multidisciplinary approaches on treatment adherence, psychiatric stability, and oncologic outcomes represents an important priority for future research.

Overall, advancing research in these areas will be essential to move from descriptive associations toward clinically actionable strategies capable of improving outcomes for patients facing the dual challenge of BD and cancer.