Neuropsychiatric manifestations of prostate cancer and its treatment: Biological mechanisms and psycho-oncology perspectives

Abstract

Prostate cancer (PCa) is the most frequently diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Beyond its oncological burden, PCa is increasingly recognized as a condition with profound psychiatric and neurocognitive implications. Depression, anxiety, sleep disturbance and cognitive decline are highly prevalent among patients, particularly those undergoing androgen deprivation therapy or chemotherapy. The most consistent clinical evidence suggests associations between androgen deprivation therapy and mood-related morbidity, whereas findings for cognition and proposed mechanisms such as inflammation, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation and altered neural signaling remain heterogeneous and are not uniformly supported by PCa-specific prospective studies. Addressing these dimensions requires a holistic, multidisciplinary model of care in which mental health screening and psychiatric support are integrated into oncology practice. PCa thus serves as a paradigm for understanding the bidirectional relationship between chronic disease, treatment-induced biological stress and psychiatric health. This narrative review links evidence on treatment-related neuropsychiatric outcomes, proposed biological mechanisms, neuroimaging findings, societal aspects of neuropsychiatric morbidity in PCa, while also highlighting important areas for integrated care and future research. Sources such as PubMed/MEDLINE, Scopus, Web of Science, PsycINFO, Google Scholar and reference-list screening were used to identify English-language peer-reviewed literature published from January 2000 to November 2025.

Key Words: Prostate cancer; Depression; Anxiety; Androgen deprivation therapy; Cognitive impairment; Neuroinflammation; Oxidative stress; Psycho-oncology

Core Tip: Prostate cancer and its treatment can produce substantial neuropsychiatric consequences that extend beyond conventional physical and oncological outcomes. The available evidence supports routine recognition of psychological distress and targeted evaluation of mood and cognitive symptoms in higher-risk patients. Mechanistic biomarkers, neuroimaging approaches and precision psycho-oncology strategies remain important areas for further prospective validation. This narrative review distinguishes direct prostate cancer evidence from indirect mechanistic context and emphasizes practical psycho-oncology assessment alongside research priorities in neuroimaging, biomarkers and longitudinal care. We further highlight neuroimaging approaches, global disparities in psycho-oncological care and emerging brain–tumor communication pathways.

INTRODUCTION

Prostate cancer (PCa) is one of the most commonly diagnosed malignancies among men worldwide. According to GLOBOCAN 2022[1], approximately 1.47 million new PCa cases and 397430 deaths were estimated worldwide, with an estimated 5.03 million men living within five years of a PCa diagnosis. The Lancet Commission on PCa projects a substantial increase in the global disease burden over the years; with annual new cases expected to rise from approximately 1.4 million in 2020 to 2.9 million by 2040, while annual PCa deaths are projected to increase by approximately 85% from 375000 to nearly 700000[2]. In India, nearly 37948 new PCa cases were estimated in 2022, corresponding to an age-standardized incidence rate of approximately 5.6 per 100000 men[3]. A recent study further suggests a continuing upward trend in India, with the age-standardized incidence rate estimated to reach approximately 9.15 per 100000 by 2031[4].

Despite the clinical management of PCa has focused majorly on physical distress, psychological and neuropsychiatric outcomes are increasingly recognized as important components of the overall disease burden. Psychological distress have been reported in 10%-38% of PCa patients globally, while a substantial proportion of men show significant distress and of those with clinically meaningful distress continue to report unmet psychological support needs[5].

Although neuropsychiatric and cognitive outcomes have been increasingly recognized among men with PCa, the available evidence remains heterogeneous across disease stages, treatment modalities, assessment methods and study designs. Previous review studies have frequently focused on androgen deprivation therapy (ADT) or on specific psychological outcomes, this narrative review examines neuropsychiatric outcomes across the PCa continuum, from diagnosis and localized disease to advanced and metastatic disease, while considering the effects of major treatment modalities, particularly ADT, systemic therapies, chemotherapy, radiotherapy and surgery. Specifically, it asks what is currently known about psychiatric and cognitive outcomes across the PCa trajectory, which proposed biological mechanisms are supported by direct human evidence and how this evidence can inform psycho-oncological assessment and supportive care. It further discusses psychiatric and cognitive outcomes that are linked to PCa and its main treatment options, biological mechanisms that are relevant such as neuroinflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, changes in neural signaling and alterations seen in neuroimaging, along with psycho-oncology approaches for screening, providing supportive care and managing treatment in an integrated way. Therefore, this narrative review integrates evidence from clinical studies, neurobiology, neuroimaging and health systems while clearly separating established findings from observational associations, indirect evidence about mechanisms and emerging hypotheses.

METHODOLOGY

Study design

This narrative review applied a structured literature-search and evidence-synthesis approach protocol based on guidelines often used for scoping and narrative reviews. We used the Population-Concept-Context framework to frame the review scope. The population included men diagnosed with PCa (both currently treated patients and PCa survivors).

The concept of interest was the set of psychological, neuropsychiatric and neurocognitive effects relevant for PCa and treatment, as well as the suspected biological, neuroimaging, and psychosocial effects responsible for them. The context included oncology and psycho-oncology clinical and research practices worldwide, with a particular interest for evidence originating from India and other Asian regions when regional information was provided.

Search strategy

Electronic literature search was performed on PubMed/MEDLINE, Scopus, Web of Science, and PsycINFO. Google Scholar was also searched as a search resource and reference lists of all relevant systematic reviews, meta-analyses and prominent primary studies were scanned for other applicable studies. A comprehensive search included all publications from January 2000 until November 2025.

Inclusion was extended to include publications in 2025, to ensure all available recent clinical, mechanistic, brain imaging and psycho-oncology data were included for the purposes of generating this review. Prior to 2000, studies were included when their importance as key foundational research on the established concept, test criterion or biological mechanism was noted. Search terms included combinations of Medical Subject Headings, database-specific subject headings and free-text terms. The principal search concepts included: (“Prostate cancer“ OR “prostatic neoplasm“ OR “prostate neoplasm“) AND (“depression“ OR “anxiety“ OR “psychological distress“ OR “neuropsychiatric“ OR “cognitive impairment“ OR “cognitive decline“ OR “sleep disturbance“ OR “quality of life“) AND (“androgen deprivation therapy“ OR “ADT“ OR “chemotherapy“ OR “radiotherapy“ OR “radical prostatectomy“ OR “systemic therapy“).

Additional targeted searches were performed for mechanistic and care-related domains using terms including“HPA axis“, “neuroinflammation“, “cytokines“, “oxidative stress“, “neural signaling“, “neuroimaging“, “psycho-oncology“, “psychosocial intervention“, “screening“, “masculinity“, and “supportive care“. Search terms were adapted according to the indexing system and search functions of individual databases.

Eligibility criteria

Studies were considered eligible if they satisfied one or more of: (1) Quantitative (controlled, case-control), qualitative or mixed methods peer-reviewed research (focusing on psychological, psychiatric, neuro-psychiatric or neuro-cognitive endpoints of PCa and men; (2) Systematic reviews, meta analyses and scoping reviews in areas pertinent to these endpoints; (3) Review or qualitative accounts of neuropsychiatric treatment-related events as an adjunct or symptom of treatment in a men’s PCa cohort (PCa and ADT, surgery, radiotherapies and chemotherapies, other systemic therapies); (4) Research into the relevant biological systems proposed to link cancer/treatment with neuro-psychological function: i.e., inflammation/immune system, HPA axis, oxidative stress and neural pathway disruption, neural/blood brain signaling and alteration from neural/radiological imaging; (5) Studies examining psychological screening, supportive-care models, support mechanisms (both individuals and teams); and (6) Support group approaches. Qualitative studies were included when they contributed evidence regarding patient experiences, psychological or emotional distress, treatment-related concerns, masculinity, coping, or unmet supportive-care needs.

Studies were excluded if the individual case studies or minor case series that lack wider generalizability; conference abstract abstracts submitted for presentation at scientific congresses not with an accompanying article in a peer-reviewed, full-text publication or pre-prints that are not peer-reviewed prior to circulation. editorials or commentary which do not contain original data and original primary data; studies involving cancers other than PCa when PCa-specific data could not be separately extracted. Reports in languages other than English were excluded as they could not be translated by the group or independently verified.

Articles for which the full text could not be accessed were not used for detailed evidence synthesis. Non-peer-reviewed sources were excluded from clinical and mechanistic conclusions. Exceptions were made for authoritative epidemiological, public-health and guideline sources, including the International Agency for Research on Cancer (IARC), World Health Organization (WHO), national cancer registries, and recognized professional organizations.

Literature identification and study selection

Titles and abstracts were retrieved from database and hand-searching searches. Identified references were reviewed for inclusion based on the scope and eligibility criteria. Potentially relevant studies were then full-text retrieved for review.

Reference lists of selected literature on landmark systematic reviews, major well-cited original reviews, and well-conducted original studies are also reviewed for inclusion if they did not emerge in other searching strategy, especially in narrative literature search. Since the objective of this narrative review was to synthesize a series of clinically and biologically diverse areas rather than estimate a pooled treatment effect, the selection criteria focused on relevance, the soundness of the study’s methodology, its directness and its contributions to the specific themes identified in the review rather than simply including every reference found in the search.

Evidence prioritization and assessment

Evidence was prioritized according to the clinical or biological question under consideration. For clinical outcomes, greater weight was given to systematic reviews and meta-analyses, large prospective or longitudinal cohort studies and well-designed PCa-specific observational studies. For therapeutic and psycho-oncology interventions, randomized controlled trials and systematic reviews were prioritized where available, followed by prospective intervention studies.

Experimental cell and animal studies were used as primarily supporting mechanistic context, and were considered insufficient alone to demonstrate a clinical causal role. PCa-specific evidence was prioritized over findings extrapolated from other malignancies or general oncology populations. Evidence from non-PCa populations was used only when necessary to provide mechanistic context and was identified as indirect evidence.

For neuroimaging outcomes, PCa-specific longitudinal and treatment-associated studies were given greater interpretative weight than small cross-sectional studies. For psychological and qualitative outcomes, greater weight was given to studies with clearly defined populations, validated assessment instruments, and adequately described disease stage and treatment characteristics. Priority has been given to research that uses clearly defined populations and/or validated instruments/qualitative and structured measures. Studies that are specifically linked to disease and stage have taken priority over general ‘at large’ (and not clearly defined) population studies.

Global epidemiology and healthcare claims have had priority given to data sourced from IARC/GLOBOCAN; WHO, the WHO Report, or IARC Handbooks of Cancer Screening; to cancer incidence registries from national organisations; reports of International Commissions; international clinical guidelines; major population-based surveys; in lieu of any narrative reports.

Since this narrative review incorporated heterogeneous evidence across clinical, observational, qualitative, neuroimaging and mechanistic study designs, no single formal risk-of-bias instrument was considered applicable across the entire evidence base. Evidence priority was applied on the basis of following factor: (1) Study size; (2) Study design; (3) Methodology quality; (4) Direct relevance to PCa; (5) Consistency with previous literature; and (6) Relevance to clinical question and replication of the results in independent populations. Accordingly, associations identified in observational studies were not interpreted as evidence of causality, and mechanistic hypotheses based primarily on preclinical or indirect evidence were distinguished from findings supported by human clinical data.

Data synthesis

Study design, patient characteristics, stage of PCa (where available), type of treatment received, psychiatric or neuropsychiatric outcome measure, biological or neuroimaging measures, and major study conclusions were harvested from the chosen literature. Since the studies, particularly with respect to the population examined, the treatment utilized, the outcome measure chosen, the design employed, and the “mechanistic” endpoints assessed were considerably heterogeneous, formal statistical pooling was not conducted. Studies were synthesized along thematic lines and reviewed in relation to four key areas: (1) Psychosocial/emotional effects of PCa diagnosis and trajectory; (2) Treatment-related neuropsychiatric and cognitive effects; (3) Biological/neuroimaging mediators linking PCa/treatment to psychiatric outcome; and (4) Psycho-oncology screening/supportive-care strategies and potential future clinical directions.

When results varied-for example, as when contrasting positive and negative study outcomes related to specific questions, the general trend and shortcomings of opposing conclusions were described rather than stated as a sole conclusion. Clear distinctions were made between well-established clinical findings and such issues as observational correlations, the indirect evidence of the “mechanistic links”, and nascent postulates/theories.

Methodological limitations

Given this is a narrative literature review, not a systematic review study, the search was focused on broad and clinically useful coverage, rather than attempting a full search for all possible papers. As with narrative reviews generally, selective literature identification and study prioritization may introduce citation-selection and interpretation bias. Likewise, limiting searches to English-only publications probably resulted in language bias, with evidence from certain areas perhaps being under-represented.

Since there was no formal risk of bias study-level assessment, the quality of the individual studies across the different sources could not be easily compared. These limitations of the review should be considered when viewing the strength and interpretability of the evidence presented.

THE NEGLECTED PSYCHOLOGICAL DIMENSION

PCa research has advanced in oncological control, thus improving survival rates, but the psychological aspects of the disease are still not very well understood. The probable reasons for this are the stigma and the ignorance attached to mental health issues. The diagnosis of cancer is obviously a very tough situation, and the patients are likely to feel depressed (18%-35%) and anxious (up to 40%), especially if they are on ADT[6]. Men, due to societal expectations about masculinity, often do not express their suffering or ask for help; thus, they concentrate on the recovery of the body rather than the adjustment of the mind[7]. Mental health evaluations are rarely conducted during the management of PCa, a situation that leads to adverse clinical consequences, like the patient quitting treatment and the chances of the cancer coming back increasing. The application of psycho-oncology practices, such as counselling and resilience training, is a sure way of promoting survivorship and improvement in quality of life overall.

The concept of onco-psych neurobiology

The onco-psych neurobiology study shows the significant links between the biology of PCa, neuro-endocrine control, immune interaction, and mental health. Among recent findings, cancer has been termed systemic, thus claiming an interplay of brain, endocrine and immune systems[8]. The stress of psychological origin posts the HPA axis into action, and when it is fully activated, the cortex gets the first signal for cancer and negatively nurtures tumor biology through both angiogenesis and immune control[9]. It is particularly in the case of patients on ADT that the imbalance becomes acute and persistent cortisol leads to the onset of mood disorders[10]. Besides the major pro-inflammatory cytokines like interleukin (IL)-6, the patients also suffer due to the worsening of fatigue and depression caused by the cytokines[11]. The psychological stress pathway dealing with cancer is the β2-adrenergic one, which opens the way to use β-blockers like propranolol for relief from these effects[12]. The aggressive nature of tumors and unfavorable prognosis is associated with the presence of high levels of β-adrenergic receptors, and stress-responsive factors may even lead to the occurrence of castration-resistant PCa[13]. Cognitive Behavioral Stress Management is a promising method for correcting biological disturbances. Beyond this need, the coupling of longitudinal studies with neuroimaging to clarify the relationship between psychological distress and cancer outcomes is a strong hold[14]. On account of tumor biology and psychological factors, the multidisciplinary approach in treating PCa is the way to go for better patient outcomes.

Beyond the tumor: Psychological toll of PCa diagnosis

The PCa diagnosis is often a very drastic and unsettling event for a man in terms of his psychological and neurobiological balances. It is no longer only the question of the physical presence of the tumor but also the reactions of the mind and body to the existential, physiological, and relational aspects of living with a cancerous tumor. Thus, the psychological effects of PCa have been promoted to the status of major determinants of quality of life, treatment adherence, neuroendocrine integrity and long-term survivorship outcomes, while previously they were considered to be just “side-effects”. The proper understanding of the overwhelming emotional distress, the adaptation of coping strategies, the changes in one’s identity, and the dynamics of fear is a requirement for the creation of the integrative care models that align with the onco-psych neurobiological paradigm mentioned earlier.

Emotional responses to diagnosis

The instance when a patient gets a PCa diagnosis is the starting point of a series of emotional, thought and bodily responses. First of all, anxiety comes almost instantly: Usually, men experience many thoughts running on their minds, increases in their body’s sensitivity, constant thinking about death or loss of health, and great confusion about the outcome and the options for treatment[15]. Later, they might fall into the depression which has a variety of symptoms including feeling low all the time, not getting any pleasure from things, feeling tired and disrupted sleep, not just as sadness in response to external factors but as a different emotional state that is connected to hormones and inflammation mediators[16]. Most importantly, new data from big cohorts have shown that PCa patients are practically twice as likely to receive a formal diagnosis of an anxiety disorder as control subjects of the same age-group, with the greatest difference being in the case of the patients on androgen-deprivation therapy themselves or those having a higher-risk disease[6]. The constant activation of the stress mechanisms the HPA axis and the sympathetic nervous system causes the production of cortisol to rise, the tone of noradrenaline/adrenergic to increase, and thus a prolonged “fight/flight” physiology which is the opposite of emotional control getting stronger and faster “allostatic load” accumulation[17]. These neurobiological changes come out as body symptoms (such as heart beats pounding in the chest, disturbed sleeping and waking patterns, and feeling very alert all the time) which, on their part, add to the psychological distress[18]. Such factors as severity of illness, method of treatment, mental health history, social support systems, and beliefs about masculinity and vulnerability in the respective cultures determine the intensity and duration of this emotional suffering. If this acute psychological response is not detected and treated promptly, it may eventually lead to chronic distress, delayed recovery and more complicated situations.

Coping and adaptation mechanisms

PCa coping is a process that may involve various kinds of strategies such as cognitive, behavioral, and socio-emotional ones. Among the different ways of coping, those with problem-focused reactions, emotional regulation, and social support make up the healthy group and are linked to healthier physiological responses and consequently better overall well-being[19]. Besides, maladaptive coping which is composed of avoidance and emotional suppression is associated with negative health outcomes. It has been shown that psychological resilience is a dominant factor when it comes to maintaining well-being during adversities, and it is found that higher resilience is linked to lower anxiety and better quality of life[20]. Education, income, and social connections are the factors that enhance resilience while comorbidities and low socioeconomic status are the ones that hinder coping. Moreover, psychological flexibility is the one that helps to moderate the relationship between fear of recurrence (FCR) and distress, particularly in men on ADT[21]. It can be concluded that the overall adaptation to PCa is a complicated interrelation of psychological, social and biological factors.

The FCR and mortality awareness

FCR is one of the most difficult psychological issues that PCa survivors have to deal with, and it often lasts even after clinical remission. Some people continue to be very aware of their bodies and misinterpret little signs as indicators of relapse while they stress out more than usual when waiting for the results of a prostate-specific antigen test[22]. This situation called “watchful waiting” has a negative impact on the brain’s threat detection areas, which subsequently activates stress systems that lead to physiological problems such as inflammation and disruption of sleep, ultimately reducing the quality of life. FCR is a condition recognized as a consequence of mortality awareness, which is the reason for the resulting distress and changing the priorities in one’s life, as well as having the physiological effects in the form of inflammation and immune function[23]. To tackle FCR, clinical approaches based on psychoeducation and the therapeutic management of anxiety and threat perception are among the options[24]. However, if the situation is not well managed, FCR might continue to be a chronic stressor.

Impact on identity and self-perception

The diagnosis and treatment of PCa are the areas which had the strongest impact on male identity and self-esteem, mainly owing to the symbolic and biological significance of the prostate. One of the main causes of the erosion of masculine self-esteem are the adverse effects of treatments, which include sexual dysfunction, infertility, change in body composition and psychological distress. A patient undergoing ADT will have a way lower self-esteem and a way higher level of depression compared to a patient not on ADT[25]. The combination of the morphological and hormonal changes plus the societal demand might lead a man to withdraw socially and enjoy less of a normal life[26]. In contrast to the finer living notion of masculinity, many men rather find it in emotional connections. Psychotherapy and supportive behavioral interventions still play a huge role in clinical practice as they assist in the restoration process of self-concept and relational satisfaction[27]. In the context of PCa treatment, recognizing identity disruption is critical alongside the management of oncologic side effects, which in turn will require extensive interventions for holistic patient-centered care (Table 1)[28-41].

Table 1 Represents the summarization of the evidence of psychological and neurocognitive outcomes.

Treatment modality	Psychological neuropsychiatric outcomes	Key findings	Quantitative estimates	Ref.
Active surveillance	Anxiety, depression	Most men show stable, low levels of psychological distress over time, although a minority experience clinically relevant symptom	Anxiety prevalence: Up to 23%-24%; depression prevalence: Approximately 12.5%	Watts et al[28], Alvisi et al[29], van den Bergh et al[30]
Radical prostatectomy	Mental distress, depression, anxiety	Persistent psychological distress may occur after surgery and is associated with urinary and sexual dysfunction and reduced quality of life	Approximately 8%-20% may require psychological support	Köhler et al[31], Ilie et al[32], Meissner et al[33], Mehnert et al[41]
Radiation therapy	Depression, anxiety	Psychological morbidity may be lower than with watchful waiting or ADT, although depression and anxiety remain clinically relevant	Not consistently reported across the cited studies	Ravi et al[34], Crump et al[35]
ADT	Depression, anxiety, cognitive impairment, reduced quality of life	ADT is associated with increased psychiatric and cognitive morbidity and reduced physical, social, and functional well-being	Depression: RR = 1.51; anxiety: HR = 2.08; cognitive impairment: RR = 1.45	Saini et al[36], Siebert et al[37], Galvão et al[38], Crump et al[39]
PCa- depression associated – healthcare burden	Depression-associated healthcare utilization	Comorbid depression is associated with substantially greater emergency care, hospitalization and mortality among men with PCa	ER visits: OR = 4.45; hospitalization: OR = 3.22; mortality: HR = 2.82	Jayadevappa et al[40]

Active surveillance and androgen deprivation therapy are the periods where anxiety and depression are most evident, though the majority of surveillance groups experience longitudinal stability while a delicate subgroup continues to suffer with persistent distress. Androgen deprivation therapy still stands as the strongest factor that predicts and leads to depression, anxiety, poor cognitive functioning and living with a low quality of life, the impact of which will be felt not only in the first year of treatment but also later on. Besides post-prostatectomy distress and radiation-related mood shifts that are considered additional factors contributing to the overall morbidity, the point about the necessity of integrative psycho-oncologic care is brought about more strongly. ADT: Androgen deprivation therapy; PCa: Prostate cancer; RR: Relative risk; HR: Hazard ratio; OR: Odds ratio; ER: Emergency room.

THERAPEUTIC INTERVENTIONS AND NEUROPSYCHIATRIC SEQUELAE

The survival rates have risen due to modern PCa treatment, yet the neuropsychiatric and cognitive effects have gained more significance for the quality of life. The intricate biopsychosocial scenario of the PCa patients includes hormone therapy, chemotherapy, radiation therapy, and the nervous system. Besides, tumor metabolism modulation, neuroendocrine balance adjustment, neuroinflammation and brain plasticity are some of the areas that have been influenced by the medical interventions, and thus, they affect mood, cognition, and behavior. That is why it is so important to understand these effects, as they will help in providing comprehensive care.

ADT and mental health

ADT is one of the primary therapies for advanced PCa and is usually accompanied by LHRH agonists that drastically lower testosterone levels. Although ADT has been associated with potentially altered structure and function of the brain, cognition and emotion the evidence is insufficient and inconsistent in nature. Experimental MRI study indicated reductions in gray-matter volume at regional levels following six months of ADT in 12 men. Another small PET study, using TSPO as a marker, found no differences in the levels of brain inflammation between men with and without reported cognition impairments with ADT use[42,43]. In view of this, cognitive decline, microglial reactivity, HPA axis disruption, changes in neurotransmitters and the presence of “brain fog” should be regarded as potential but unconfirmed effects requiring validation in adequately powered longitudinal human studies. The decrease of hormones excites inflammatory responses in the body that have a bad influence on the generation of new neurons and on mood[44]. Low androgen levels have been shown to cause microglia activation and oxidative stress, which are characteristics of the despair-related behaviors in the laboratory animals[45]. Neuropsychiatric side effects would be more pronounced for patients who already suffer from cardiovascular or metabolic disorders. ADT has been reported in neuroimaging studies as causing significant structural brain changes within months, especially in the hippocampus and prefrontal cortex, producing symptoms like tiredness, loss of feeling, and difficulty in thinking[43]. The inflammatory response to the treatment is indicated by raised cytokines that support inflammation and are responsible for the hindrance of neurogenesis and the development of mood disorders[46]. Trials of therapies indicate that regular exercise[47], CBT, and intermittent ADT can work together to reduce the cognitive and emotional problems by enhancing the neuroendocrine balance and neurotrophic signaling (Table 2)[28,31,32,35,37,39,41,48-50].

Table 2 Risk factors and predictors of psychological morbidity in prostate cancer.

Risk factor	Psychological outcomes	Effect size/association	Statistical significance	Ref.
Divorced relationship status	Anxiety	Higher prevalence of clinically relevant anxiety among divorced men (56.3%) compared with the overall cohort (23.1%)	P = 0.011	Watts et al[28]
High-risk PCa	Depression, anxiety	Major depression: AHR = 1.82 (95%CI: 1.75-1.89); anxiety disorders: AHR = 1.96 (95%CI: 1.87-2.05)	P < 0.001	Crump et al[35], Crump et al[39]
ADT	Depression, anxiety, cognitive impairment	Depression: RR = 1.51; anxiety: AHR = 2.08 (95%CI: 1.93-2.25); cognitive impairment/dementia: RR = 1.45	Depression: P = 0.0002; anxiety: P < 0.001; cognitive impairment: P = 0.024	Siebert et al[37], Crump et al[39]
Younger age (per 10-year decrease)	Depression	OR = 1.38 (95%CI: 1.16-1.60)	P = 0.001	Fervaha et al[48]
Poor social support/absence of caregiver	Anxiety, depression	Absence of caregiver: OR = 5.02; emotional support: OR = 0.81; instrumental support: OR = 0.67	P < 0.05	Mehnert et al[41], Morris et al[49]
Moderate-to-severe urinary dysfunction	Mental distress	OR = 4.79 (95%CI: 1.04-22.03)	P < 0.05	Ilie et al[32]
Poor relationship satisfaction/sexual difficulties	Psychological distress	Lower relationship satisfaction associated with greater distress; OR = 0.14 (95%CI: 0.03-0.77)	P < 0.05	Köhler et al[31], Ilie et al[32]
Pre-existing depression or anxiety	Depression	OR = 3.64 (95%CI: 2.42-5.48)	P < 0.0001	Fervaha et al[48]
High-risk disease classification	Depression	OR = 1.49 (95%CI: 1.05-2.12)	P = 0.027	Fervaha et al[48]
Poor performance status (ECOG > 1)	Depression	OR = 5.01 (95%CI: 3.49-7.20)	P < 0.0001	Fervaha et al[48]
Cancer-related/treatment-related fatigue	Psychological burden, Reduced quality of life	Fatigue prevalence: 42% with ADT, 21% after radical prostatectomy, 40% after radiotherapy	Reported with 95%CIs	Luo et al[50]

It provides a brief summary of the demographic, clinical, treatment-related and psychosocial factors associated with depression, anxiety, mental distress, cognitive impairment, and poor quality of life. The strongest predictors were high-risk disease, androgen deprivation therapy, younger age, poor social support, urinary and relationship problems, pre-existing depression and anxiety, poor performance status and treatment-related fatigue. The literature reports varying levels of association from modest to strong (e.g., odds ratio up to 5.02, adjusted hazard ratio up to 2.08). ADT: Androgen deprivation therapy; PCa: Prostate cancer; aHR: Adjusted hazard ratio; RR: Relative risk; OR: Odds ratio; ECOG: Eastern Cooperative Oncology Group.

Chemotherapy and cognitive decline

PCa which has been the stronghold of non-chemotherapy treatments has gradually shifted with docetaxel, cabazitaxel, and platinum-based drugs being among the most used agents with advanced and castration-resistant patients[51]. Chemotherapy-induced cognitive impairment is where the concern lies and with the term “chemo brain” usually referred to it as such, the attention, processing speed, executive function, and verbal memory are the areas affected. Neuroimaging studies mention the presence of signs of neurotoxicity in the form of changed brain areas of the treated patients like connectedness of default mode network and thickness of cortex reduced[52]. The blood-brain barrier is another factor that chemotherapy can come across and it is a pathway to neurotoxicity through oxidative stress, mitochondrial damage, and disruption of synaptic signaling as well as raising levels of cytokines [IL-1β, IL-6, tumor necrosis factor alpha (TNF-α)] systemically that lead to neuroinflammation and microglial activation[53]. All these factors adversely affect the function of oligodendrocytes and the process of myelination leading to a scenario where cognitive deficits are permanently established[46]. Furthermore, chemotherapy-induced anaemia, fatigue, and endocrine issues lead to more difficulty for cognitive functions such as memory and attentiveness to get restored[54]. The next generation of anti-androgen therapies, including enzalutamide, apalutamide, and abiraterone, have similarly been linked to cognitive side effects due to their action on central androgen receptors[55]. Various research into preventive measures is under process, majorly focusing on factors such as aerobic exercise, neuroprotective pharmacological agents such as omega-3 fatty acids, and cognitive rehabilitation to support compensatory neural mechanisms[56].

Radiotherapy and neuro-behavioral changes

Although prostate being anatomically far away from the brain, radiotherapy can still cause neurobehavioral function indirectly through the mechanisms of inflammation all over the body, injury to the blood vessels changes in the signaling between the hypothalamus and pituitary gland[57].

The application of external beam radiotherapy and brachytherapy result in the liberation of cytokines which are believed to modify the neuroinflammatory processes hence the occurrence of side effects like exhaustion, low mood and memory difficulties during the period of treatment[58]. Clinical trials establish a connection between fatigue that is a result of the treatment and the heightened presence of IL-6 and TNF-α, while oxidative stress might interfere with blood flow to the brain mostly in older males with the vascular problem[59]. The application of monitoring tools indicates that there are momentary attention lapses and possibly chronic executive dysfunction among the radiation-treated patients. Since prostate radiation therapy is confined to the pelvis, there is no direct evidence that it irradiates the hypothalamic-pituitary axis. Although prospective studies reports might identify consistent, sustained dysfunction of cognition or treatment-induced fatigue associated with pelvic radiation, but their relation to true neuroinflammation, changes in neurotransmitters or hypothalamic-pituitary dysfunction are still not being causally explained by pelvic radiotherapy itself[60-62]. These should, therefore, be termed potential side effects from treatment burden, particularly when radiotherapy is combined with ADT, rather than as established radiotherapy-induced mechanisms[63].

Biological mediators of treatment-induced neurotoxicity

PCa treatment has complex neuropsychiatric effects that involve biological processes such as hormonal changes, inflammation, and oxidation, all of which finally affect neural plasticity and cellular metabolism. On the one hand, ADT eliminates hormones leading to a fall in testosterone and estradiol which acts as a disturbance in the pathways regulating the mood[64]. On the other, the treatments are simultaneously leading to the rise of proinflammatory cytokines that cause the blood-brain barrier to be less penetrable and to impair the conduction of signals between neurons (synaptic transmission)[65]. Finally, oxidative stress as a result of treatment compounds the problems with the mitochondria (that generate energy) and the brain as a whole. Among the genetic predispositions, it is the APOE ε4 that is considered a major risk factor. All these complexities have come together to create a situation where the combination of hormone-related problems and inflammation become the main factors reducing mental health[66]. The direction of research to come will be towards treatments protecting the nervous system such as anti-inflammatory drugs and neurotrophins enhancers that would counteract the above-mentioned effects without any compromise to cancer therapy.

NEUROBIOLOGICAL LINKS BETWEEN PCA AND PSYCHIATRIC DISORDERS

PCa and mental health issues like depression, anxiety, and cognitive decline are closely linked through far more than just psychosocial struggles[67]. Research work suggests a two-way neurobiological relationship in which cancerous processes, immune responses, and hormonal imbalances are simultaneously acting with the brain’s emotions, stress, and cognitive functions[68]. The HPA axis, signaling from inflammatory cytokines, neurotransmitter imbalances, and direct molecular interactions between the tumor microenvironment and the central nervous system (CNS) are all in play along the same path. These new findings suggest that PCa not only affects the emotional state of the organ but also alters the neuropsychiatric traits of the affected individuals through its impact on the brain’s stability.

HPA axis dysregulation and stress response

The HPA axis is vital for managing the body's reaction to stress because it operates through the combination of mechanisms, which includes endocrine, immune, and neural axes. In PCa, the situation is such that the stress caused by lack of psychologic and physiological relief leads to continual activation of the HPA axis and therefore increased production of the respective hormones – corticotropin releasing hormone, adrenocorticotropic hormone, and cortisol[9]. One of the results of this process, also called hypercortisolemia, is the reduction of the size of the hippocampus, and at the same time, it alters the function of the glucocorticoid receptors that are involved in mood regulation, thus contributing to the development of mood disorders[69]. ADT changes the HPA axis communication by virtually removing the inhibiting power of the testosterone in terms of glucocorticoid production; this then increases the likelihood of depression and anxiety[70]. Neuroimaging techniques have shown that there is a change in the activation of the amygdala and a decline in the capacity of the prefrontal cortex to control the situation, which all correspond to the PCa patients with higher levels of cortisol[71]. Moreover, the overactivity of the glucocorticoid receptors leads to the death of cells, which can be associated with neurodegenerative diseases and chemo brain. Theoretical models suggest that the HPA axis dysregulation is the culprit which intertwines psychological stress with systemic inflammation and cancer invasion, as the glucocorticoids are the ones who not only enhance the event of angiogenesis and immune evasion, thereby, possibly, quickening tumor growth and aggravating mental health problems (Figure 1)[13,18,72-78].

Figure 1 Represents hypothalamic-pituitary-adrenal axis and sympathetic signalling in the context of prostate cancer cellular processes. Author-assembled schematic integrating hypothalamic-pituitary-adrenal axis activation, sympathetic/adrenergic signaling, cortisol-glucocorticoid receptor signaling and downstream prostate cancer (PCa)-associated responses. Direct evidence from PCa patients includes altered stress/cortisol profiles[18], associations of circulating interleukin-6 and tumor necrosis factor-α with disease extent and progression[73] and clinical evidence linking glucocorticoid receptor expression/signaling with antiandrogen resistance[74-76]. PCa preclinical/cellular evidence supports stress-induced β-adrenergic signaling, tumor growth, migration, and dissemination[13,77,78]. Asterisks indicate downstream links that have not been established as causal pathways in PCa patients and are supported predominantly by PCa cellular/preclinical studies or broader mechanistic cancer literature. CRH: Corticotropin releasing hormone; ACTH: Adrenocorticotropic hormone; NK: Natural killer; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; TGF: Transforming growth factor; ROS: Reactive oxygen species; AR: Androgen receptor; EMT: Epithelial-mesenchymal transition.

Inflammatory and immune pathways

Inflammation acts as a major factor connecting PCa and neuropsychiatric disorders. The cancerous prostate cells together with the immune cells that infiltrate the site produce and secrete cytokines IL-1β, IL-6, IL-8, and TNF-α, which are able to affect the signaling in the CNS and may interfere with the blood-brain barrier[79]. In the brain, inflammatory mediators can induce neurobiological changes related to depression, such as reduced production of new neurons and increased alteration of neurotransmitters’ activity. PCa patients are more prone to suffer from fatigue and cognitive dysfunction due to the high concentrations of IL-6 and C-reactive protein in their blood[80]. Furthermore, inflammation may be one of the reasons that cancer treatments have such serious negative psychological effects, as they not only cause but also keep the cycle going by affecting the emotional and motivational circuits[81]. Presently, scientists are looking at anti-inflammatory methods as a means to limit these psychiatric problems and also to enhance the overall cancer treatment result via neuroimmune interaction[82].

Neurotransmitter alterations and mood dysregulation

Neurotransmitter systems such as the serotonergic and dopaminergic pathways that are involved in emotion and cognition control are majorly influenced by PCa and its treatments[83]. Testosterone is operating as a neuromodulator by heightening the sensitivity of the serotonergic receptor and thus stimulating the production of dopamine in the mesolimbic system[84]. In contrast, the withdrawal of androgens leads to a decrease in serotonin levels in the dorsal raphe nuclei and dopamine signaling in the nucleus accumbens, thus causing depressive symptoms[85]. Current findings point to changes in the binding of dopamine and GABA/glutamate ratios in patients receiving ADT, somewhat analogous to alterations seen in major depressive disorder[86]. Besides the cancer-related chronic inflammation, tryptophan metabolism is shifted to neurotoxic by-products leading to over-activation of NMDA receptors and neuronal health impairment[87]. Cancer treatments, such as chemotherapy and radiotherapy, not only damage the already fragile balance of the neurotransmitter system but also generate oxidative stress[88]. and cause mitochondrial dysfunction which are the main contributors to these problems[66]. The whole process is quite complicated and the result is an unstable mood and deteriorating cognitive function; however, new possible solutions such as dopaminergic agents and exercise are emerging, which might help in the restoration of the neurotransmitter balance[44].

Brain-tumor communication axis

In the field of molecular oncology, a recent development has been the discovery of a “brain-tumor communication axis” that goes cellular communication between the tumor and the CNS through neural, hormonal, and immune pathways. PCas express adrenergic and cholinergic receptors that can detect neural signals, and therefore, tumor activity can be influenced[89]. Tumor-generated extracellular vesicles (EVs) carrying micro-RNAs[90], for instance, mir-21 and mir-146a can not only reach but also influence the CSF and neuroinflammation[91]. Functional magnetic resonance imaging (fMRI) research in PCa survivors represents an emerging but limited field, with studies primarily focusing on the neurological effects of ADT. Chao et al[70] conducted one of the first prospective studies, demonstrating that while ADT did not affect cognitive test performance over 6 months, it significantly impaired brain activations during cognitive control tasks and decreased functional connectivity between the medial prefrontal cortex and other cognitive control regions. More recent research by Plata-Bello et al[92] expanded this work using resting-state fMRI, finding that ADT patients showed altered amplitude of low-frequency fluctuations and regional homogeneity compared to controls, with increased functional connectivity in multiple brain regions, suggesting compensatory mechanisms or impaired neural efficiency. However, as noted in a comprehensive review by de Ruiter and Schagen[93], the evidence remains preliminary, with only small studies published to date and methodological concerns including lenient statistical corrections for multiple comparisons. The field would benefit from larger sample sizes, comprehensive neurocognitive testing, and multimodal MRI approaches to better understand the neural mechanisms underlying cognitive changes in PCa survivors, particularly those receiving hormonal treatments. Therefore, psychophysical studies based on MRI have reported a shift in brain connectivity in case of PCa survivors[93]. More so, neuro immunological studies have shown the vagal and sympathetic pathways involved in feedback loops that connect peripheral inflammation to emotional regulation[94]. Having an idea about this axis, new therapeutic strategies by means of β-adrenergic antagonism and micro-RNA-targeted approaches to both tumor progression and neuropsychiatric well-being could be opened up. The β-adrenergic–microRNA axis is a tangible target of prospective prostate-cancer research. Though, preclinical studies associate link β-adrenergic signaling to angiogenesis, tumor progression, treatment resistance and neuroendocrine differentiation, while miR-196a may contribute to β2-adrenergic receptor–associated tumor-cell plasticity[95-97]. However, the evidence remains predominantly preclinical or observational; therefore, β-adrenergic antagonism, miRNA-targeted therapy, anti-inflammatory treatment and biomarker-guided psychiatric care should be considered hypothesis-generating rather than near-term clinical strategies. Controlled prospective trials are mandated to determine their impact upon cancer outcomes and neuropsychiatric health (Figure 2)[42,70,78,92,95-102].

Figure 2 Depicts the brain-tumor communication through autonomic, hormonal, extracellular-vesicle, and inflammatory signaling in prostate cancer. Author-assembled schematic illustrating likely bidirectional communication pathways between the prostate tumor, systemic signalling and the brain. Published human data in prostate cancer (PCa) include observations of decreased medial prefrontal activation with a relationship between Medial P-F activation and connectivity and treatment with androgen deprivation therapy[70,92], as well as altered systemic inflammation and symptom burden during treatment[98], a pilot of neuroinflammation in androgen deprivation therapy recipients[42] and circulating PCa extracellular vesicle miRNAs, like miR-21-5p[99]. From PCa cell and animal studies come evidence that autonomic innervation regulates tumor function[78] and the role of exosomal miR-146a-5p signaling within the prostate tumor environment[100]. Asterisked neuroinflammatory links – including microglial activation, astrogliosis, and their relationship with behavioral or neural effects – have not been established in PCa patients and are extrapolated primarily from non-prostate-cancer tumor-bearing animal models[101,102]. The therapeutic implications shown are exploratory research directions rather than established psycho-oncology interventions; β-blocker evidence in PCa is observational rather than interventional[96]. CNS: Central nervous system; ADT: Androgen deprivation therapy; HPA: Hypothalamic-pituitary-adrenal; EVs: Extracellular vesicles; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; CCL2: Chemokine (C-C motif) ligand 2.

THE ROLE OF PSYCHO-ONCOLOGY AND INTEGRATED CARE MODELS

Healthcare professionals may find it beneficial to include mental health when offering protocols for treatment. The recent coronavirus disease 2019 pandemic has increased the prevalence of mental health disease (MHI). Meta-analysis research found that 25% of people had severe stress from the pandemic, whereas a global cross-sectional survey found that 50.9% of individuals had anxiety features and 58.6% had depression[103,104]. Given this, estimates of the prevalence of major depressive disorder range from 13% to 16.3%. Compared to 4% in the general population, 13%-20% for cancer patients[105]. Even when a pre-cancer diagnosis psychiatric care use is taken into consideration, patients with cancer have a markedly higher risk of suicide than the overall population[106]. Cancer patients’ commitment to therapy may suffer if their mental health requirements are not addressed[37].

Treatment-related neuropsychiatric complications in PCa

However, a person’s health and quality of life can frequently be impacted by therapy side effects. Radiation can exacerbate obstructive symptoms, and surgery can increase the risk of permanent impotence or urine incontinence[107]. Patients with PCa who receive ADT are more likely to experience depression and cognitive impairment[108]. Patients who were hospitalized for MHI prior to receiving a cancer diagnosis and had PCa [hazard ratio (HR): 2.23; 95%CI: 1.69-2.94] or bladder cancer (HR: 2.18; 95%CI: 1.62-2.93) were more likely to die from their disease, according to a study done in Ontario, Canada[109]. Given it higher mortality rate, bladder cancer patients were more likely to commit suicide after diagnosis (HR: 1.73; 95%CI: 1.14-2.62) than patients with prostate (HR: 1.07; 95%CI: 0.90-1.27) and kidney (HR: 1.26; 95%CI: 0.79-2.02) cancers, according to a different comparative study that found a60% increase in the risk of suicidal death within the first 50 months of diagnosis[110]. According to a review of data from the Surveillance, Epidemiology, and End Results database from 1988 to 2010, male sex was linked to higher odd s of suicide in patients with kidney cancer [odd ratio (OR): 4.98] and bladder cancer (OR: 6.63). Suicide was also linked to advancing age in patients with testis, bladder, and PCa (OR: 1.03-1.06)[111].

Emotional, sexual and identity disruptions after PCa treatment

A major health concern is PCa, which is the most common disease among males in Western nations and the most common cancer among Italian men[112]. PCa is a major worry for males over 50 because of the increased risk that comes with ageing. There are many different types of PCa, from aggressive versions that can develop quickly, spread, and cause serious morbidity[113] to indolent tumors that have no effect on longevity[114]. The possibility of invasive treatments like radical prostatectomy, ADT, chemotherapy, and radiation therapy, along with their related side effects[36]. Casts long shadow over the lives of those affected, even though roughly half of diagnosed cases have a favorable prognosis.

Diagnosing and treating PCa can have significant and long-lasting effects. Mental distress can become a major burden, and quality of life frequently declines[115,116]. Particularly, erectile dysfunction and urine incontinence, which are frequent post-operative complications, impact organs that are closely related to identity and mental health[117]. ADT, a cornerstone of metastatic cancer treatment, might aggravate sexual issues and lead to emotional instability[118]. These mental and physical difficulties can have a disastrous combined effect that undermines one’s sense of self and jeopardizes close connections[119].

PCa is frequently inextricably related to the idea of masculinity, with physical modifications brought upon by treatment that may see as a decline in masculinity and the ability top or create. This intricate interaction between psychological and physical elements can significantly impact the decision-making process for treatment, requiring the patient, their partners or careers, and medical personnel beyond the tangible and sexual consequences, the mental health costs of PCa is a serious condition. There are many people with diagnosable depression and depressive symptoms (8%-25%), according to estimations, and ADT seems to increase this risk even more[120].

According to a meta-analysis looking at several cancer forms, including PCa, roughly one in four nearly twice as many patients as the general population suffer from depression. Significant loneliness and a high prevalence of anxiety have also been reported. The quality of life and treatment results are greatly impacted by these psychological issues[121].

It has also been demonstrated that psychological issues and distress symptoms brought on by cancer can have serious detrimental effects on the patient and their family. Psychiatric disorders have been linked to male adaptive coping and a typical disease behavior, which have detrimental consequences on quality of life, health behavior, and treatment adherence. Psychological issues in cancer have also been linked to an increased risk of suicide. In addition to causing emotional distress among the patient’s caregivers, emotional issues like depression and anxiety can also have a cascading effect on the family, raising the likelihood of complicated or painful bereavement among family members in the event of a patient’s death.

Mental health needs across PCa treatment trajectories

The significant psychological toll that cancer patients in the Middle East endure is becoming more widely acknowledged thanks to recent studies conducted there. High prevalence rates of social isolation, anxiety, and depression among cancer patients are often reported by systematic reviews and cross-sectional research conducted in nations like Lebanon, Egypt, and Jordan. For example, a comprehensive meta-analysis encompassing 14 Middle East and North Africa (MENA) countries revealed that there was a significant difference in the prevalence of anxiety and depression among cancer patients, with rates of 44% and 47%, respectively[122]. According to a single-Centre study conducted in Lebanon, among newly diagnosed cancer patients, moderate to severe anxiety was observed in 14.9% of cases and moderate to severe depression in 22.7% of cases; mild depression and minimum anxiety were even more common[123].

Global health inequities might make the psychological burden of cancer worse in MENA and Sub-Saharan Africa where access to psycho-oncology and supportive care remains uneven. Studies from Sub-Saharan Africa show that there is a lot of psychological distress, especially in patients who have advanced disease, have limited social support, live in rural areas, and face financial problems[124]. Evidence specific to PCa from Nigeria also shows a significant amount of depression and anxiety among patients[125]. However, research on psycho-oncology in MENA and Sub-Saharan Africa is still limited and not well connected, which highlights the need for more representation from the region and the development of psychological screening and supportive care strategies that are suitable for the culture[120,122].

NEED FOR INTERDISCIPLINARY PSYCHO-ONCOLOGY IN PCA

This is nothing new to PCa: Even before treatment, 19.7%of a sample PCa population showed signs of depression. The Canadian Longitudinal Study on Ageing, which measured mental health outcomes in a large analytical sample of 25183 men aged 45-85, found that survivors of PCa had statistically significantly higher odd of psychological distress (adjusted OR: 1.52, 95%CI: 1.09-2.11) and positive scores for depression (adjusted OR: 1.24; 95%CI: 1.02-1.51) than those without. This section will give an overview of studies on MHI conducted over the course of various PCa treatment modalities in order to better understand how to treat mental health complications both before and after PCa treatment. After that, it will go into recommendations for treating MHI complications related to with patients who have PCa[126].

The Neuro-psychiatric aspect of PCa may be better comprehended in the context of a transformative approach, psycho-oncology. Apart from enhancing psychological health, the overlap of oncology and psychiatry under a systemic umbrella may improve compliance with treatment and survival. Treatment of PCa in the future should be essentially interdisciplinary and inter professional, taking into consideration more than onco-logical treatment as demonstrated by newer international studies.

Cultural and societal dimensions of male mental health

An estimated 1.4 million men worldwide receives a PCa diagnosis each year, making it a serious global health concern. In Australia, survival rates for PCa have increased to 90.6% due to improvements in treatment, increasing the chance of survival 10 years’ following diagnosis. In the United States, the survival rate is 98%, while in the United Kingdom, it is 84%. However, a higher survival rate does not always equate to a higher standard of living. Over time, men may have severe physical and psychological problems as well as a decline in their quality of life due to their health. Bowel, urinary, and sexual dysfunction are prevalent in the 5-15 years following treatment, and survivors of PCa often suffer ongoing physical and psychological strain. PCa survivors often report ongoing physical and psychological load, with bowel, urinary, and sexual problems being prevalent in the five to fifteen years following treatment. Few studies have determined the triggers or the frequency at which men seek help, despite the fact that nearly one in two men with PCa report unmet psychological and psychosocial care needs and that psychological needs are common among PCa patients[127].

Global burden of PCa and long-term survivorship distress

Cancer stigma can result from the association of the disease with suffering and death, but it can also occur when others believe that a person’s behaviour is to blame for the sickness. This is because people are more likely to react negatively to diseases that are seen as manageable as to those that are not. People may there for react adversely if they believe that their cancer is the result of their own conduct. According to several studies, cancer patients may feel stigmatized due to their illness and may also feel self-blame or perceived guilt for the cancer’s etiology. These elements may combine to produce poorer mental health outcomes and unfavorable self-perceptions[128].

Cancer stigma, self-blame, and psychological impact

The PCa diagnosis and treatment is felt by many men as an existential threat to their sense of self, appearance, and masculinity. This intricate inter relationship between loss, in turn, generates a deep conflict of feelings. Masculine Inadequacy this is one of the few problems specifically related to men that has been clearly linked to severe distress. A strong correlation with demoralization, a distinct affective state involving helplessness, hopelessness and loss of purpose or meaning, accounts for the association between low scores of masculine self-esteem and depressive symptomatology. Masculine norms around self-sufficiency, autonomy and strength are undercut by the bodily decline and dependence on medical systems associated with PCa treatment. This affective distress emerges in interviews when patients describe feeling more unattractive and less masculine, even overtly doubting their worth as a man. The psychological symptoms can become more severe than just sadness, to the extent that a person may even develop acute emotional instability, spontaneous sadness or full-blown adjustment disorder with mood deregulation. SD can be seen as the central clinical factor through which threat to masculinity and self-esteem is mediated. It is the single most significant functional loss that men strive to reclaim, forming the focal bridge between somatic injury and psychological and relationship problems[129].

Masculinity, identity threat, and adjustment struggles

Men’s masculinity was threatened by several life transitions. The most significant of these was the unavoidable alteration in libido and sexual function. Men expressed that they felt as though they had “lost a bit of (their) manhood” after undergoing treatments like radical prostatectomy[130]. Underscoring the idea that there is the best chance of function preservation even if this lowers survival[131,132]. According to several research, men viewed post-treatment erectile dysfunction as the most significant obstacle they overcome[133]. The embarrassment associated with erectile dysfunction was exacerbated by incontinence interfering with their sexual relationships[134]. Men expressed anxiety about their uncertain futures, which made the mandatory to take control of their course in life. Additionally, some men accepted changes in their masculinity as inevitable as they aged, especially when it came to normalizing sexual and urinary symptoms. They were able to justify that alterations brought on by PCa would have occurred regardless as the greater vulnerability they experienced was also acknowledged as a result of ageing. On the other hand, other men highlighted the value of “thinking young” and believing in their own youth in order to postpone the effects of their cancer and ageing in general, representing the domain anti-death at cancer was a disease that men had to combat. Men also emphasized that having PCa had little impact on their lives and, consequently, their manhood a shame so reclaiming their masculinity[134].

Life transitions, ageing, and re-negotiation of masculinity

Men also explained why they were unaffected by PCa by describing the idea of dying with it rather than of it. Others claimed that, in spite of any unfavorable emotions they might have, it was just a fact of life that needed to be dealt with. People with sexual dysfunction also employed this narrative to minimize the impact of sex on their life by highlighting its insignificance to the more their partners. Men recognized that downplaying the impact of PCa and repressing emotions in this manner were traits associated with men[135].

Cultural barriers to mental health help-seeking in men

Many men are treating to the traditional, hegemonic masculine mechanisms when dealing with their distress. These coping strategies are often characterized by maintaining limited emotional disclosure, minimizing the impact of the disease and downplaying vulnerability. Although some men may use these early coping strategies adaptively, over-adherence to these RIEM ideals is linked with worse mental health outcomes; thus, psychological flexibility represents a clear need for intervention[136]. Internalized shame, which is the perception that functional losses violate masculine norms deters help-seeking for sensitive symptoms of sexual dysfunction. It has been documented from clinical data that a large number of patients refused to talk about their sexuality due to fears of being judged or stigmatized. In culturally specific contexts, such as the MENA, the stigma surrounding mental health is amplified by deep lying rained traditional beliefs. In Saudi Arabia, for example, psychological symptoms are frequently attributed to spiritual causes, such as witchcraft or spirit possession. This cultural framing of mental illness discourages individuals from pursuing conventional psychiatric treatment, leading many to prefer spiritual healers or traditional therapies, thereby creating a substantial systemic barrier to professional psycho-oncology care.

Adaptive coping, emotional flexibility, and resilience pathways

The patient’s ability to psychologically adapt – to become a “survivor” rather than remaining a “patient” – depends critically on moving away from rigid, functional definitions of masculinity. Men who cope effectively utilize cognitive reappraisal, employing a “trade-off” rhetoric (health preservation justifies sexual loss) and re defining sexual intimacy in relational or non-penetrative terms. This successful adaptation allows them to reaffirm their masculine identity through non-functional domains, such as acting as a family protector, mentor, or taking active control over their health. This profound psychological restructuring must be actively facilitated by specialized interventions[136,137].

Enhancing support services and overcoming utilization barriers

A major contributing factor to men’s delayed help-seeking behavior is cultural stigma and beliefs, which frequently cause them to appear only when their sickness is advanced[137,138]. Men’s perceptions and attitude as regarding PCa may be influenced by prevalent societal myths and beliefs[139]. All of them atoning the region urgently need to implement extensive awareness and early detection programs. Strong political commitments are required to support these initiatives and increase men’s understanding of the significance of PCa screening and management. These initiatives should aim to inform men about prostate health, debunk stigmas and misconceptions about the condition, and promote routine screening. A number of suggested initiatives from the analyzed studies that aim to raise awareness of PCa and encourage early identification in the Sub-Saharan-Africa region are compiled in this section[140].

While most men with PCa are not active “support-seekers”, they are likely to be active “information-seekers”. Actively promoting supportive services may contribute to greater awareness of them, but it might not result in higher service utilization rates. At different stages of diagnosis, treatment, and follow-up, men with PCa may need to be actively provided and encouraged to seek care, especially with relation to sexual, emotional, and psychosocial concerns[128]. For the two to three decades after the diagnosis, this treatment should also include regular follow-up visits. Given that males don’t seem to be particularly proactive about seeking out this kind of support, the researchers believe that offering this kind of support could help with both the early identification of such problems and subsequent therapy. This service can facilitate access to further therapy for men who have been diagnosed with cancer by helping them connect with an expert in mental health as soon as feasible.

BRIDGING THE GAP: FROM AWARENESS TO ACTION

Cancer incidence rates are still rising globally as a result of improvements in early identification and medical treatment of the disease during the past three decades, as well as increased population longevity[141]. In the future, more people will need palliative care, long-term monitoring, and medical treatment for cancer as a result of these trends. As a result, for many patients, cancer has become a chronic illness that can be fatal, creating additional difficulties for all-encompassing cancer care. Depending on personal requirements and expectations, these include, among other things, a shift in the patient’s role towards more active involvement in treatment decisions and treatment itself. Considerable toxicities brought on by treatment may result in psychosocial distress, considerable short-term and long-term side effects, and functional loss in a variety of behavioral and life domains. Consequently, patients’ functional status and quality of life may be significantly diminished, and they and their families deal with several coping and adjustment issues[138].

Prevalence and consequences of emotional distress

Cancer patients’ psychosocial suffering is a major worldwide issue that affects people in a variety of resource contexts and to differing degrees. However, this important part of cancer care has not received enough clinical and research attention. One According to research, a significant percentage of cancer patients (35%-80%) suffer from psychological distress, which includes anxiety (10%-40%), depression (5%-30%), and a reduced quality of life, regardless of the course of the illness, the patient’s location, or the healthcare environment. Between 20% and 30% of cancer patients are thought to have a mental illness, with adjustment disorders, anxiety disorders, and depressions being the most prevalent. Cultural, economic, political, national, international, and healthcare system issues all have a substantial impact on the experiences of individual patients. There are significant and unethical differences between high-income and low-income populations both inside and between nations globally, and psychosocial distress transcends both national identification and country-income levels[142].

Socioeconomic, cultural, and healthcare system inequities

The need to fully comprehend and meet the unmet supportive care needs across a variety of populations is highlighted by the rising global incidence of cancer[143]. A multifactorial, unpleasant experience of a psycho logic (i.e., cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment is what the National Comprehensive Cancer Network defines as emotional distress[144]. For cancer patients around the world, emotional discomfort presents serious obstacles that affect their quality of life, general health, and clinical results. Notably, there are regional differences in the prevalence ranges of emotional discomfort. According to the United Nations, high-income countries in the Global North – which includes Israel, Japan, South Korea, Australia, New Zealand, and Northern America – generally indicate prevalence of 30%-50% for emotional distress[145]. On the other hand, the prevalence rates of emotional distress are generally between 20% and 70% in the low-income nations of the Global South, which include Africa, Latin America and the Caribbean, Asia (apart from South Korea, Japan, and Israel), and Oceania (apart from Australia and New Zealand)[146].

Determinants of psychosocial care-seeking behavior

The increased frequency of emotional discomfort seen in the Global South is probably a result of larger unmet psychosocial requirements, notwithstanding the paucity of studies examining variations in the effects of unmet psychological needs in various resource situations. Even after controlling for medical co morbidity, metastatic status, and treatment, the co-morbidity of severe anxiety and depression with cancer has long been known into dramatically increase healthcare utilization and annual healthcare costs. It also lowers the quality of life for patients. Additionally, there is typically a dyadic interaction between patients’ emotional anguish and their family members’ and careers’ emotional pain, which exacerbates the psychosocial effects of cancer. In addition to creating financial burden and raising the possibility of medicalized poverty or homelessness, this also entails making family dynamics and decision-making more difficult. Although they frequently face serious mental and physical difficulties themselves, careers are essential in helping patients during their cancer journey[138].

Need for global integration of psycho-oncology into cancer care systems

Access to mental health services is still restricted in many places, especially in low-income and middle-income nations where resources are limited, despite growing awareness of the significance of attending to psychosocial requirements in cancer care. Because opioids are highly unavailable or have restricted access, managing cancer pain is extremely difficult in many low-income or middle-income countries. In order to solve these issues and guarantee fair access to supportive care on a worldwide scale, it is therefore thought that institutions like the WHO must be involved in order to influence countries and develop policies. This means incorporating psycho-oncology care methods into the regular medical curriculum and acknowledging them as essential skills in cancer management[144].

In addition, socio economic level variations and the gap between n urban and rural areas where access to psychosocial services and health information may be restricted due to physical constraints and a lack of qualified professionals can further worsen this inequality. Their experiences are further marginalized by poverty, which frequently exacerbate so the previously marginalized identities. People who belong to racial, cultural, or ethnic minorities, for example, could have additional interpersonal, institutional, and structural obstacles to receiving psychosocial care[145].

Patients’ tendency to seek psychosocial support has been associated with factors like age, socio economic status, and disease stage, underscoring the significance of focused therapies[146]. In addition, research carried out in Australia and the UK have found perceived obstacles to receiving supportive care services, such as difficulties obtaining information and navigating intricate care systems.

FUTURE PERSPECTIVES: NEUROPSYCHIATRIC RESEARCH IN ONCO- MENTAL HEALTH

Despite frequently having lower cancer incidence, those with severe mental illness (SMI) had more than 30% higher cancer mortality rates than the overall population. A number of variables, such as delayed diagnosis, limited access to cancer screening and treatment, and worse general health among people with SMI, are likely contributing to the greater cancer mortality in the psychiatric community. However, it has also been proposed that early ageing and mortality in this population may be the cause of the decreased incidence fold age cancers in SMI. Furthermore, it has been found that people with mental health challenges have a noticeably greater incidence of some diseases, including breast and lung cancer. Multiple factors, such as unhealthy eating habits, smoking, and adverse drug reactions, are linked to this elevated risk. According to data, psychosocial stress may also have an impact on the incidence and/or mortality of cancer. Stress-induced neuro endocrine signaling pathways that impact anti-tumor immune cells and foster an immune suppressive and pro tumor milieu are among the possible plausible mechanisms[147].

Psychiatric medications and cancer: Risks and protective effects

The prevalence of psychological conditions in oncology patients is the main reason for the use of psychiatric drugs in this population[148]. A surprising and encouraging connection between psychiatric drugs and cancer treatment has been shown by an expanding body of research in recent years[149]. A higher incidence of acute myeloid leukemia was associated with hematological adverse effects in clozapine-treated patients. Conversely, on the other hand, despite the substantial carcinogenic characteristics of alcohol and cigarettes, psychiatric patients do not appear to have a higher incidence of cancer than the rest of the population. Approximately 80% of people with schizophrenia smoke cigarettes and consume alcohol. In fact, this cohort is seeing a decline in brain and gastrointestinal malignancies[150].

Neuropsychiatric symptoms as early indicators of tumor biology

New research, however, suggests that these symptoms are not coincidental but rather play a crucial role in the pathogenesis of tumors through immune-mediated, metabolic, neuro-chemical and structural processes. Because psychological symptoms frequently precede tumor identification, delaying the initiation of suitable oncological treatment and continuously affecting treatment compliance and prognosis, the phenomena mentioned above has significant therapeutic ramifications[151]. When brain tumors cause psychiatric symptoms, the CNS is a key focus. These symptoms can range widely in clinical presentation, from mild cognitive and personality changes to severe affective deregulation, psychosis, and catatonia. During the course of their illness, 30%-70% of patients with primary or metastatic brain tumors report having clinically significant psychological symptoms, according to epidemiological research[152].

Neuroimaging advances: Gyrification, structural changes, and cognitive effects

Recent years have seen the use of cortical gyrification, a sensitive imaging marker in the brain’s early stages, to detect cortical changes brought on by cancer[153,154]. The right fusiform, paracentral, precuneus, superior, middle temporal gyri, and left pars opercular is, all exhibited greater gyrification than the left superior parietal gyrus and left cuneus gyrus, according toa study of older breast cancer survivors conducted five to fifteen years following chemotherapy[155,156]. Cognitive composite scores for visual vocabulary the Doral reading recognition based on prior learning experiences showed negative correlation with the increased right paracentral gyrification[156] demonstrating long-term cognitive impairments associated with chemotherapy in older cancer survivors.

Biomarkers for psycho-oncology: Molecular, immune, and imaging signatures

In order to identify potential novel treatment targets and the biological processes underlying a disease, biomarkers are essential. They can be utilized for disease monitoring, prognostic estimation, therapy outcome prediction, and cancer screening in healthy patients. “A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or a conditioner disease”, states the National Cancer Institute. Known as a molecular marker or signature molecule, it can be used to determine how well the body reacts to a treatment for a disease or condition. In epidemiology, it can also be helpful to decrease the misclassification of exposures and diseases, improve the identification of exposure-disease relationships, or expand intervention opportunities, finally converting test results into a relevant public health application[157].

Integrating biomarkers, imaging and artificial intelligence into precision psycho-oncology

Several distinct biological processes that correspond to various tumor kinds and anatomical sites cause tumor vascularization, which happens concurrently inside the same cancer tissue. Heterogeneous vasculature that depends on angiogenesis to sustain a sufficient blood supply and diffuse invasion into the healthy parenchyma is a characteristic of gliomas. This milieu, which supports tumor growth and invasion through intricate network interaction, is made up of stem cells, immune cells, non-transformed or reactive glial (and neural) cells, and mesenchymal cells at the cellular level. Crucially, the microvasculature plane is where glioma angiogenesis and its various hemodynamic characteristics alter. In order to better understand tumor biology, computed tomography perfusion in vivo imaging can shed light on physiological processes that may prove crucial supplemental to conventional morphologic imaging in predicting neuro- oncological outcomes. It can also be beneficial for evaluating how different therapies are working[158].

In recent years, bioinformatics applications of artificial intelligence (AI) have proliferated across all fields of inter disciplinary study. The robustness and accessibility of data causal inferences, explanatory ability, visualization models, and medical imaging are all significantly enhanced by AI technologies. A subset of machine learning called deep learning has improved capture as an approach that has been effectively applied to decode image-based puzzles, such as those in medical imaging. A documented approach of choosing model hyper parameters without ever using data or an unannotated dataset from the test is one of these contributions from AI methodological interpretation. Additionally, all patient demographics, medical conditions, and various cohorts or ethnicities are included in multi-institutional data. For comparisons to have statistical power, the test set should ideally contain at least a few hundred samples, or possibly thousands of data for optimal statistical power. Additionally, external validity can be established with the use of confidence intervals of the given performance indicators[159].

Personalized risk stratification models that combine immunological profiling, neuroimaging, and AI-driven behavioral analytics are being created in the field of psychiatry to identify high-risk individuals, customize mental therapy, and improve functional recovery over time. To guarantee that psychiatric optimization is a crucial component of precision cancer therapy, neuro-oncology psychiatry is exploring the use of prediction models[160].

Correlation data with unclear sequence or directionality largely support a range of causal-mechanistic connections, including cytokine signatures, or exosomal biomarkers. AI-based models are still in their infancy and will need to be improved because there is a chance that different imaging techniques, preprocessing methods, and the demographic makeup of imaging datasets will provide biased results[161].

In the discipline of the diagnostic, molecular imaging is essential and paramount. It illustrates how therapy and imaging visualization can be enabled concurrently or sequentially by combining a therapeutic marker with a diagnostic implementation. Insightful biomarkers with the sensitivity to capture each patient’s distinct clinical picture are created and constructed to provide a number of benefits in clinical applications for non-invasive and treatment responses throughout time. In addition to broadening, the scope of therapeutic applications for patient diagnosis, therapy, and specific management of the underlying tumor biology, this niche may present a promising new method for imaging biomarkers in neuro imaging, directing treatment and facilitating personalized refining. This could provide a promising new avenue for molecular imaging and the imaging of biomarkers unique to cancer types in order to achieve phenotypic therapeutics in the future of precision medicine[162].

DISCUSSION

This review indicates both psychological and neurocognitive issues of clinical significance occur after being diagnosed with PCa, but no unique, consistent, and straightforward linear cause-effect relationship emerged. Issues of distress, anxiety, depression symptoms, sleep impairment, sexual and relationship issues, and cognitive complaints occur at various time points in the clinical trajectory and are modulated by a myriad of factors, including cancer stage and history of treatment, age, premorbid psychological health and neurocognitive function, comorbidity, social support and availability of healthcare services. The review of a large, community-based sample of prostate-cancer survivors noted the relationship between distress and emergency-department utilization and all-cause mortality after control for demography, medical, functional, and healthcare services, but it’s important that the observational nature of the study does not determine the effects on causation[163].

The strongest clinical implication is therefore not that psychological distress directly accelerates tumor progression, but that it is an important marker of patient burden and unmet supportive-care needs. Prevalence estimates require careful interpretation because the frequency of distress depends on the study’s choice of screening measure, screening cut-off point, sampling frame, and time during the course of illness at which the measure is obtained. Measures of distress from questionnaires are not equivalent to clinical diagnoses, and registration of a mental health diagnosis may not accurately reflect the level of symptoms experienced by patients who have not sought mental health care.

Additional variability in age, education, disease severity, treatment burden, comorbidity, cultural expectation, and level of comfort with discussed of sensitive issues including: Body-image, sex, or emotion among studies can also obscure our interpretation of the findings. A systematic review of 31 studies found that 16 studies reported no adverse cognitive effect, 11 reported a negative effect, and four were inconclusive[164]. Previous systematic review and meta-analysis of 14 studies in 417 ADT patients showed an impaired performance in visuomotor function but the impact was statistically non-significant in six other cognitive function[165]. These results are suggestive of a potentially non-uniform neurotoxicity not evident or hard to assess.

Several characteristics may account for the inconsistencies among studies. Baseline cognition, age, education, cardiovascular and metabolic risk, depression, fatigue, sleep disturbance, pain, medication, disease burden and concurrent treatments may have affected cognitive testing and indirectly, the likelihood of receiving ADT. Other studies vary by length of follow-up, neuropsychologic domains studied, sensitivity of tests used, practice effects, comparisons groups and definition of cognitive impairment. Timing of cognitive assessment may be especially significant: The meta-analysis conducted by McGinty et al[165] demonstrated that the magnitude of these deficits was greater in shorter follow-up studies, and that effects were not observed in most other cognitive domains. Hence, subjective self-report of cognitive complaints and objective neuropsychological performance should be reported as related, but separate variables.

Neuroimaging-based evidence is biologically interesting, although limited. In one prospective observational cohort of 36 men recruited, with 30 follow-ups; neither decline on working-memory or cognitive-control tests was observed after six months of ADT[70]. Similar investigators noted reduction of medial prefrontal activation and decreased connectivity to other cognitive-control-related regions on FMRI[70].

The importance and validity of these changes relative to the context of this study remains unknown as according to the investigators “further study is required to answer questions of long-term relevance”[70]. Such shortcomings might provide explanation for the results in the 2021 systematic review whereby the utilization of fMRI was linked with changes, however, non-significant to the measured neurocognitive outcome[164]. Furthermore, the combination of both techniques can provide an insight into this issue.

The hypothesized biological pathways-androgen withdrawal, inflammation, oxidative stress, HPA axis activation, sympathetic signaling and changes in neural plasticity-appear plausible, but this review does not provide sufficient evidence to define a prostate-cancer-specific causal relationship. Many observed mechanistic events are cross-sectional or translational and/or they emerge from studies which preclude temporal ordering; cytokine signatures, adrenergic signaling, EV signalling and neuroimaging outcomes should, consequently, be characterized as proposed mechanisms or research biomarker candidates. Adrenergic blockade, anti-inflammatory treatment, neuroprotectants, biomarker-guided therapy and AI models will only be validated investigational approaches if future, prostate-cancer specific trials yield reproducible patient benefit with acceptable safety.

The observed associations of distress with compliance, health care utilization, cancer progression, and mortality also require careful interpretation. Reverse causality is probable: Worsening cancer, treatment toxicity, pain, fatigue and functional decline may elevate distress while simultaneously decreasing adherence and increasing healthcare contact. Confounding by age, stage, comorbidity, baseline psychiatric illness, socioeconomic disadvantage, social support and treatment may also contribute to observed associations. In the identified cohort of patients with more distress in the survivor groups a higher rate of health care utilization with increasing age and higher rate of mortality were noted, but the interpretation remains cautious since it was purely observational data, even with risk adjusted variables and exclusion of deaths during the first two years[163]. This is not to suggest using this data to establish the relation between psychological distress, recurrence of cancer, loss of sensitivity of treatment or mortality.

Treatment-related factors should be interpreted in context. Surgery or radiotherapy may impact quality of life as a result of urinary, bowel, sexual and fatigue associated effects, whereas ADT produces sustained sex-hormone suppression and is often prescribed to patients with higher-risk disease. Patients with these advanced cancers receive chemotherapy or newer systemic therapies for which factors such as disease burden, anemia, pain, polypharmacy, concurrent ADT, prior treatment may cause similar problems such as fatigue, sleep disturbance, emotional/mood problems and cognitive effects. Therefore, a comparison of treatments would need to compare risk stratum and not individual treatment options in isolation.

The clinical evidence supports routine distress assessment and appropriate referrals rather than universal psychiatric treatment in the cancer care context. Oncology distress management guidelines promote the integration of psychosocial care into general care for patients diagnosed with cancer and the identification of cancer patients referred for assistance and intervention[166]. Within the context of PCa screening, assessment should include: Baseline diagnosis, as patient transitions into treatment and in survivorship as applicable to the phase of cancer care. Significant symptomatology (mood symptoms) sleep disturbance, psychiatric illness, fatigue or a large treatment burden, vascular or metabolic risks or reported cognitive change may benefit from targeted evaluation of mood, sleep, medication effects, and cognition.

The equity and acceptability of care are also crucial to successful implementation. Poor help-seeking behaviour stemming from societal gender expectations of behaviour, stigmatization, limited emotional disclosure, poverty, rural isolation, shortages of training skills and culturally specific explanations of mental illness may reduce help-seeking. Screening unaided is unlikely to improve outcomes where services are inaccessible or poorly adapted to local language and cultural context. Therefore, effective care pathways also need to promote integrated care, including established links and sharing arrangements for scarce special care resources, awareness of carer needs and effective delivery of culturally adapted emotional, sexual and cognitive information.

Future studies should employ adequately powered longitudinal cohort and intervention studies. Studies should assess baseline neurocognition and psychiatric history before therapy; record ADT exposure, treatment regimens, disease state and comorbidities; utilize similar cognitive and patient reported outcome measures; and consider education, sleep, fatigue, depression, medication use, cardiovascular risk and socioeconomic status. Neuroimaging and molecular biomarkers should be considered exploratory until shown to be reproducible, add clinical value and demonstrate external validity. Predictive models should be prospectively validated across institutions and samples, with clear reporting of model calibration, missing data and performance in underrepresented groups. Intervention trials should define patient-centered outcomes clearly and should not assume that reducing distress will necessarily alter cancer-specific survival.

CONCLUSION

PCa and its treatment can impose profound emotional, cognitive, sexual and interpersonal consequences the extent to and the determinants of which will depend on individual patient characteristics and treatment center, most of which is still not evidence-based. The strongest and most reasonable clinical recommendation is routine assessment for distress and risk-factor/symptom based screening in appropriate patients for problems of mood, sleep, fatigue, cognition and sexual or relational adjustment if positive which should then initiate readily available, culturally acceptable and coordinated care across the spectrum of specialist support including the oncologists, mental health professionals, rehabilitators, sexual health specialist and/or social service providers[166].

Existing evidence does not establish psychological distress as a cause of prostate-cancer recurrence or progression, or that integrating psychiatric care independently improves survival. ADT-related cognitive findings are inconsistent, and neuroimaging, inflammatory markers, molecular signatures and predictive models should be considered research priorities rather than clinical tools[70,164,165]. A patient-centered model that treats mental health and quality of life as integral components of prostate-cancer care is justified, while extrapolating to tumor control and survival should remain limited to evidence from appropriately designed causal studies.