Endocrine Biomarkers of Suicidality in Schizophrenia

Suicide is a major cause of early mortality in patients with schizophrenia. Although standard risk assessments consider well-known clinical factors such as past suicide attempts, depression, hopelessness, substance use, command hallucinations, and agitation, these factors do not completely explain why some patients are at high risk for suicide while others are not.

Biomarkers have therefore emerged as a promising way to supplement clinical judgment with objective, measurable factors that could improve risk assessment, leading to more individualized interventions to prevent suicide.

Our study focuses on endocrine biomarkers, as there is a close relationship between the endocrine system and stress, metabolism, inflammation, sleep, and brain function––all processes implicated in schizophrenia and suicidality. Investigating these biomarkers may provide insight not only into the biology of suicide in schizophrenia, but potentially into the illness itself. We reviewed existing literature on the associations between endocrine biomarkers and suicidal ideations, behaviors, and attempts in schizophrenia, with the goal of identifying markers that may ultimately contribute to predicting and preventing this tragic outcome.

Identified Biomarkers

We reviewed the literature examining endocrine biomarkers associated with suicidal ideation, attempts, or suicide death in schizophrenia. A PubMed search identified 226 reports; 31 remained after title screening, and 14 directly relevant studies were included after abstract review. Overall, suicidality was associated with dysregulation of several endocrine pathways.

HPA-axis dysfunction

Changes in the hypothalamic-pituitary-adrenal (HPA) axis function were found consistently. Data from several studies showed that patients with schizophrenia who had a history of suicide attempts had higher baseline and post-dexamethasone cortisol levels. One study also identified higher baseline cortisol in patients who later made suicide attempts. However, findings on dexamethasone nonsuppression were later found to be inconsistent.^1,2

Thyroid-axis abnormalities

Changes in thyroid hormone levels were also linked to suicidality. Data from a study involving drug-free men with schizophrenia showed that free thyroxine (free T4) levels were significantly higher than those of control patients, and suicidal ideations were more common among those with elevated free T4 levels.

Prolactin

Interestingly, prolactin levels were elevated in patients with schizophrenia overall, but were not particularly increased in patients with schizophrenia who were suicidal. This suggests that suicidality may be specific to certain endocrine pathways rather than reflecting a general hormonal imbalance.³

Gonadal-axis abnormalities

Results concerning testosterone were particularly noteworthy. Male patients attempting suicide had significantly lower testosterone levels than healthy controls. Those who used violent methods had even lower testosterone levels than those who attempted suicide using nonviolent means. Patients with schizophrenia who had attempted suicide showed the lowest testosterone concentrations, which were significantly lower than those of a separate group of men with schizophrenia who had not attempted suicide.⁴

These findings challenge the usual belief that higher testosterone is linked to greater impulsivity and aggression. The authors suggested that self-directed violence might operate through different mechanisms than violence against others, leading to important questions about our understanding of the biological basis of aggression and suicide.⁴

Neurosteroid abnormalities

In a postmortem study of individuals with schizophrenia and bipolar disorder who died by suicide, pregnenolone—a neurosteroid influencing GABA signaling—levels were significantly lower in the parietal cortex compared to patients with schizophrenia and bipolar disorder who died from other causes. This finding remained significant when focusing on the schizophrenia subgroup alone, even though the number of schizophrenia suicide cases was small.⁵

Clues From Clozapine and Lithium

Examining endocrine biomarkers also highlights agents with antisuicidal effects, particularly clozapine and lithium, and may reveal the mechanisms behind these effects.

Clozapine’s ability to reduce suicide risk is generally linked to its superior management of psychosis, along with reductions in depression and aggression. Its unique serotonergic and dopaminergic effects also play a role. However, the endocrine findings present another possibility: Part of its benefit may involve the stress and neurosteroid systems that seem abnormal in suicidal patients. Findings from small studies indicate that clozapine can alter nocturnal cortisol secretion, and other study data have shown that it can increase pregnenolone levels in the hippocampus and cortex.^6,7 Pregnenolone and its related neurosteroids may work therapeutically through their effects on neuroplasticity, inflammation, and HPA-axis regulation.⁷ The finding that cortical pregnenolone was lower in patients with schizophrenia who died by suicide suggests a possible endocrine mechanism that contributes to clozapine’s antisuicidal effects.^5,7

Lithium’s antisuicidal effects are more established in mood disorders than in schizophrenia, although some limited data exist for this population.^8,9 Nonetheless, lithium is relevant because it also affects several endocrine pathways discussed in our review. Our findings showed a link between higher free T4 and increased suicidality, while hypothyroidism is a known effect of lithium treatment.³ Although this does not establish a causal relationship, the overlap raises interesting questions for further research. Moreover, human data indicate that lithium can alter ACTH and cortisol responses to dexamethasone/CRH challenges, whereas animal studies show increased allopregnanolone and a trend toward higher pregnenolone.^10,11 A 2026 in vitro study further reported dose- and time-dependent changes in pregnenolone, progesterone, DHEA, and related neurosteroids following lithium exposure.¹²

Taken together, these findings encourage exploration of the antisuicidal properties of these medications and whether we can better understand, replicate, and potentially optimize these mechanisms in novel psychopharmacological agents.

How Does This Impact Clinical Practice?

Endocrine biomarkers should not replace structured clinical assessment, and additional studies are needed before any changes in clinical practice can be recommended. Specifically, studies are needed to better establish causality and clarify the endocrine mechanisms associated with suicide.

Future studies should therefore examine endocrine biomarkers and suicidality longitudinally, allowing for greater temporality and a better understanding of potential causal relationships. This could include studies of patients treated with clozapine or lithium, in which different endocrine parameters are tracked alongside symptom response and suicidality. Such studies could provide further information about the mechanisms underlying both suicidality and the antisuicidal treatment effects of clozapine and lithium.

If causal relationships between endocrine biomarkers and suicidality can be more clearly established, the next question will be whether these markers have predictive and preventive value. Future trials could determine whether tracking these biomarkers—and intervening in response to endocrine changes—may improve clinical outcomes. These conclusions could then support the development of clinical, evidence-based guidelines.

Concluding Thoughts

Our review suggests that suicide in schizophrenia is linked to issues across various endocrine pathways. Although current research does not establish causality, the findings point to biologically plausible pathways that need further investigation. This may prompt a reevaluation of the connections between endocrine dysfunction, the pathophysiology of psychosis, and suicide risk. Thus, endocrine markers may help identify patients with schizophrenia who are at high risk for suicide.

Dr Mourani currently serves as chief resident of the clinical neuroscience research unit at Yale School of Medicine in New Haven, Connecticut.

Dr Nasrallah is professor of psychiatry, neurology, and neuroscience, as well as vice chair for faculty development and mentorship, at the University of Cincinnati College of Medicine in Ohio.

References

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