Suicide Risk in Glioblastoma Multiforme: A Brief Review of Risk Factors, Screening, and Prevention

Patient Demographics

Several demographic factors have been consistently associated with suicide risk in patients with GBM. Older age has been identified repeatedly across multiple analyses. One analysis of Medicare data found that 82.8% of suicides in those with GBM were by patients 44 years and older, and another study found that intracranial malignant cancers identified older age (60–79 years old) to be an independent risk factor for suicide, with a standardized mortality ratio (SMR; SMR = number of observed outcomes/number of expected outcomes) of 3.54. [4, 5]

In addition to age, gender has also been found to be a risk factor. One surveillance-based study in GBM found that 93.1% of those who died by suicide were male. Other studies have identified male gender as an independent risk factor for suicide in GBM with a SMR of 1.78. These estimates reflect suicide deaths rather than suicide attempts. Many suicide attempts are nonfatal, with mortality varying substantially by method. [6, 7] No studies in the GBM population have accounted for the burden of suicidal ideation and suicide attempts.

Male gender and older age are risk factors for suicide in the general population, and are theorized to be due to use of more lethal methods, particularly firearms. [8] In the general population, women are twice as likely to attempt suicide but men are four times more likely to die by suicide. This is theorized to be mediated by suicide method by demographics: older males are more likely to use firearms, which are highly lethal. Women are more likely to attempt suicide by overdose, which is less frequently successful, a pattern sometimes referred to as the “gender paradox” in suicide, in that women attempt more, but succeed less, and vice versa. These findings may also apply to patients with GBM, but no literature systematically has measured attempts, only completions. [8]

Socioeconomic risk factors have not been studied in the GBM population, though a large SEER analysis of cancer patients found that Medicaid-insured (SMR 1.72), uninsured (SMR 1.66) were associated with significantly higher suicide risk, and another study showed that patients from the lowest-income counties had persistently higher suicide risk even > 10 years post diagnosis. [2, 9]

Tumor Characteristics

Studies evaluating malignant intracranial tumors- a broader category that includes GBM and other aggressive primary brain neoplasms- have found that supratentorial tumor location is independently associated with suicide. [5] Glioblastoma histology itself has the highest risk among brain tumors (SMR 4.05). [5]

This association may reflect the neurocognitive and functional deficits associated with tumors in this region. Approximately 90% of patients with supratentorial tumors will experience neurocognitive dysfunction. [10] These tumors are associated with higher rates of motor and executive dysfunction and personality change, which is theorized to impact activities of daily living, work, and independence. [4] In a retrospective study, tumors involving the frontal lobe are significantly associated with postoperative depression scores, [11] further supporting that location not only affects neurological functioning, but also psychiatric disease incidence.

Demoralization

Demoralization is a clinical construct that is not formally recognized as a Diagnostic and Statistical Manual (DSM) diagnosis. It is characterized by subjective helplessness, hopelessness, and a desire to give up, and is distinguished from major depression by the absence of persistent low mood or anhedonia. Although no published studies have specifically evaluated demoralization in GBM, evidence from the broader oncology population suggests clinical relevance. In a study of 430 oncology patients, demoralization occurred in 21% of patients, but demoralization co-occurred with either a mood or anxiety disorder in only 7% of the sample, meaning that roughly two-thirds of demoralized patients did not have an anxiety or mood disorder. In this study, demoralization was associated with a relative risk of 2.0 (CI 1.1–3.5) for suicidal ideation when controlling for mental disorders such as anxiety or mood disorders. [12] Another cross-sectional study of 303 cancer patients in China found that both demoralization and depression were independent risk factors for suicidal ideation (demoralization with odds ratio (OR) of 5.85; depression with OR of 6.68), but these findings were not controlled for confounders. Furthermore, a recent systematic review identified demoralization as a significant risk factor for suicidal ideation in cancer patients. [13] Due to findings such as these, the National Comprehensive Cancer Network (NCCN) Distress Management Guidelines explicitly list existential distress/demoralization as a distinct entity and recommends screening for and addressing this concern. [14]

Timing and Prognosis

Suicide risk does not appear to follow a linear trajectory after GBM diagnosis. Multiple studies have identified the highest risk to be within the first year of diagnosis, with risk generally decreasing with time. One study identified a SMR of 3.05 (95% CI, 2.04–4.37) within the first year, compared with 1.17 (95% CI: 0.82–1.63) thereafter. [4] Similarly, another study found that death by suicide was highest in the first year after diagnosis (SMR = 13.04) although this was not an independent predictor after adjustment. [5] In contrast with these findings, a prospective cohort study in brain cancer patients found suicidal ideation peaked between 6 and 9 months post-diagnosis, suggesting that suicidal ideation may actually increase several months after diagnosis. [15]

In the GBM population, several explanations have been proposed for the apparent decline in risk over time. These include the psychological shock from initial diagnosis, improved psychosocial support with time, improving symptom management, and methodological concerns such as competing mortality risk. [16, 17 In dementia patients, progression of disease with physical and cognitive decline has been theorized to be protective against suicide, though this has not been considered in the GBM population. [18] By extension, cognitive decline and delirium, which occur in later stages of GBM, may also contribute to decreased suicide risk in this population.

Mental Health Diagnoses

In the general population, experiencing a mental disorder increases the risk of suicide. [19] Accordingly, comorbid psychiatric illness may further increase suicide risk among patients with GBM. In one prospective observational study of patients that excluded those with prior psychiatric diagnoses, suicidal ideation was significantly associated with higher depression scores, but suicidal ideation also commonly occurred in those without clinical depression. [15] Clinicians should recognize that suicidal ideation may occur independently of major depression and that screening specifically for suicidal ideation is necessary.

Medication-Related Psychiatric Effects

GBM patients are frequently treated with medications associated with psychiatric sequelae. For instance, dexamethasone is commonly used to manage peritumoral edema. Dexamethasone may produce dose-dependent insomnia, irritability, depressive symptoms, and psychosis. The ABCD trial studied oncology patients receiving dexamethasone 8 mg twice daily for 1 week, then 4 mg twice daily for 1 week. These patients experienced an increase in neuropsychiatric adverse effects in 18% of cases versus placebo. [20] In addition, GBM patients are highly susceptible to seizures, and anti-epileptic drugs (AEDs) are commonly used. While many of the AEDs are associated with psychiatric side effects, levetiracetam is among the most clinically relevant. It frequently produces non-psychotic behavioral symptoms including irritability, agitation, depression, emotional lability, with a relative risk increase of 7% versus placebo per FDA labeling. [21]

Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM. In animal models, TMZ and radiotherapy have produced anxiety- and depressive-like behaviors in mice, but in humans retrospective studies in high-grade gliomas suggested that concerns regarding TMZ’s cognitive effects are more likely due to tumor progression than TMZ itself. [22, 23 Bevacizumab is FDA approved for recurrent GBM, but it has been associated with deterioration in mood and cognition vs. placebo. [24] In GBM patients, radiotherapy is associated with neuropsychiatric symptoms, though these results are highly confounded by the fact that larger and higher-grade tumors are more likely to receive radiotherapy, and are independently associated with neuropsychiatric effects.

Evaluation and Treatment

Suicide-Reduction Strategies

As aforementioned, older men with GBM appear to be at higher risk; this is also the population that is most likely to own firearms. Lethal means counseling is strongly recommended as it improves firearm locked-storage practices. Firearms account for approximately 50% of suicides in the United States and have a case fatality rate of 85–90% [26]. Even if a patient attempts suicide by another method, other means are far less lethal. Suicide safety planning is also one of the most evidence-based brief interventions for suicide prevention. This includes identifying warning signs, internal and external coping strategies, social supports, crisis contacts, and lethal means counseling; a systematic review found that brief interventions incorporating safety planning were the most consistently associated with reduced suicide attempt rates among interventions.[27]

Treatment

For those patients who are screened, interviewed, and diagnosed with major depressive disorder, treatment may include psychotherapy and pharmacologic management. No randomized controlled trial has evaluated pharmacologic management of depression in patients with primary brain tumors, a notable gap in the literature. In fact, a 2023 pooled analysis of greater than 1700 patients found antidepressant use at chemotherapy maintenance cycle 4 was associated with poorer outcomes. [28] Another large review found that antidepressants were associated with worse survival after adjusting for covariates. [29] Both studies suggest that antidepressant use is a marker of disease severity rather than a cause of poor outcomes, such as disease progression and worsening functioning. [28, 29]

Depression itself has been shown to be independently associated with overall survival in GBM patients; patients prescribed antidepressants are those with worse survival, making it difficult to distinguish medication effects from confounding by indication. There is no outstanding high-quality evidence evaluating the effectiveness of antidepressants in improving quality of life of GBM or brain tumor patients.

Psychotherapy modalities have been shown to be effective in depressed patients with GBM and cancer in general. In GBM patients, cognitive-behavioral therapy (CBT) delivered by nurses significantly reduced anxiety and depression compared to routine care. [30] In a more generalized cancer population, a RCT of 253 patients reported that Meaning-Centered Group Psychotherapy (MCGP) significantly improved spiritual well-being, quality of life, and decreased depression, hopelessness, and desire for hastened death as compared supportive group psychotherapy. [31]

Applying these findings, a 2024 RCT directly compared MCGP to individual CBT in cancer patients and found MCGP was more effective in improving meaning in life, purpose, and life goals, and equally effective as CBT in improving depression in cancer survivors. [32] Taken together, some data directly exhibits evidence for CBT in GBM, and other modalities, such as MCGP, have been shown to be effective in patients with cancer generally.

Competing interests

Michelle Riba, M.D., M.S. is the editor-in-chief of Current Psychiatry Reports. She did not review this article for submission. Nick Waldvogel, M.D. and Hyo Ryu, D.O. have no disclosures to report.