Prolactin Monitoring for Antipsychotics and the Impact of Stress

SPECIAL REPORT: HORMONES & PSYCHIATRY

Monitoring of physical health consequences of antipsychotic drugs is becoming more common in clinical psychiatric practice. Hyperprolactinemia, one of the common adverse effects of most antipsychotics, attracts the specific attention of psychiatrists. However, in clinical practice, it remains underdiagnosed and inadequately managed.

Presentations of hyperprolactinemia differ between genders. In women, primary symptoms include low libido, sexual dysfunction, breast enlargement, galactorrhea, infertility, and menstrual abnormalities. In men, primary symptoms include erectile dysfunction, gynecomastia, and oligospermia.^1,2 In both genders, primary symptoms can include reduced bone mineral density. Other concerns are increased risk of breast cancer, prostate cancer, thromboembolism, decreased glucose tolerance, insulin resistance, and hyperinsulinaemia.^2,3

Considering the presenting symptoms and long-term consequences of hyperprolactinemia, there is a need for monitoring, and it is important to remain abreast of prolactin. It is a neuropeptide, which is considered a stress hormone, and it plays various roles in the physiological systems, including reproduction, metabolism, immune regulation, stress adaptation, neurogenesis, and neuroprotection.^4-6

A fasting prolactin level (measured at least 2 hours after waking) higher than 25 ng/mL in women and higher than 20 ng/mL in men is considered as hyperprolactinaemia.² Levels are usually under 100 ng/mL for drug-induced hyperprolactinemia, whereas levels greater than 250 ng/mL indicate the possibility of prolactinoma.⁷

Prevalence

Around 15% to 20% of women with menstrual disturbances present with hyperprolactinemia.⁸ It is more common in psychiatric patients than in the general population. The reported range of antipsychotic-induced hyperprolactinemia is between 18% to 72% in men and 42% to 93% in women.⁹ Interestingly, hyperprolactinemia has been reported in 32% antipsychotic-naive individuals at risk of psychosis and in 35% of patients with first-episode psychosis.¹⁰

Causes

Antipsychotics increase prolactin levels by blocking dopamine pathways in tuberoinfundibular tracks. Although antipsychotic-induced hyperprolactinemia is most frequently observed in psychiatry, there is a long list of causes of hyperprolactinemia, which could be physiological, pathological, or due to the adverse effects of a range of drugs.¹

Physiological states such as pregnancy, lactation, breastfeeding, neonatal period, nipple stimulation, sexual intercourse, exercise, and sleep increase prolactin levels. Prolactin levels are elevated in many illnesses, including pituitary gland tumours.^1,8

A variety of medications other than antipsychotics can increase prolactin levels. These include: phenytoin, metoclopramide, domperidone, prochlorperazine, verapamil, methyldopa, labetalol, physostigmine, estrogen therapy, ranitidine, cimetidine, morphine, methadone, apomorphine, heroin, cocaine, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, thyrotropin-releasing hormone, omeprazole, and others.^1,8

Hyperprolactinemia is more commonly associated with haloperidol, chlorpromazine, and sulpiride (not available in the US) as first-generation antipsychotics, and with amisulpride, risperidone, and paliperidone in second-generation antipsychotics. It is less frequently associated with asenapine, clozapine, quetiapine, and olanzapine.⁸

Prolactin levels also increase as a bodily stress response, following both physical and psychological stress. This aspect of hyperprolactinaemia appears not to have garnered much clinical attention. The relationship between stress and prolactin is complex, as prolactin has been reported to play a significant role in the development of stress-induced pathological changes in various organs,⁸ making it a clinically relevant area to explore.

Stress and Prolactin

Hyperprolactinemia can occur as a stress response to physical conditions such as venepuncture, hypoglycemia, myocardial infarction, surgery, and so on.^1,8,11 Similarly, psychological stress secondary to the experience of stressful events can cause hyperprolactinemia.⁸ Psychological stress is ubiquitous, and it is extremely relevant to study its impact on hyperprolactinemia, especially in patients with mental illness. While evaluating the cause of hyperprolactinemia, psychological stress needs to be considered, as it might pose a diagnostic challenge.¹² Interestingly, it has been reported that the stress of seeing a physician can increase prolactin levels. A repeat test is suggested for prolactin levels below 50ng/mL, which should be performed after a 60-minute rest in a quiet room.⁸ A study involving healthy men and women reported a significant increase in prolactin levels following a laboratory-based psychobiological stress test. With no difference between genders, the prolactin response was dependent on the general physiological stress response and on the estradiol level in women.¹¹

Psychological stress plays an important role in the pathogenesis of psychotic disorders and stress-related psychiatric disorders. Association of prolactin has been suggested in schizophrenia and related psychoses through various mechanisms.¹³ In antipsychotic-naive individuals with a high risk for psychosis and patients with first-episode psychosis, prolactin levels and self-perceived stress were significantly higher than those of the healthy controls, although there was no association of stress and prolactin levels.¹³ A possible role of prolactin in emerging psychosis has been suggested, which is linked to stress and has a comparatively stronger impact on women than on men.¹⁰

Depression also affects prolactin levels through the stress response. Prolactin levels have been reported to be higher in patients with major depressive disorder (MDD),⁶ and were correlated with symptoms of anxiety, hostility, and somatisation.¹⁴ Findings from a meta-analysis indicated a significant difference between patients with MDD and healthy controls,⁴ suggesting prolactin as a biomarker for depression. Various other associations of stress and prolactin have been reported, such as childhood adversities and hyperprolactinemia in later life of women, variation of prolactin level in posttraumatic stress disorder, and so on.⁶

The exact relationship between stress and prolactin is still unclear.^6,15 Prolactin leads to various changes in the brain during pregnancy, facilitating behavioral and physiological adaptations of a young mother, and regulating maternal emotionality and well-being.⁶ On the other hand, hyperprolactinemia can suppress ovulation, leading to childlessness. In patients with prolactinoma, hyperprolactinemia has been associated with anxiety and insomnia.¹⁶ Stress is linked to many psychiatric disorders, and prolactin, as a stress hormone, may have a significant contribution. The mechanism may be linked to dopamine, which regulates prolactin secretion.⁶

These observations suggest that there is a need for more research about stress-related hyperprolactinemia and how it is relevant for patients with psychiatric illnesses.

Monitoring Prolactin Levels

Considering the symptoms and long-term consequences of hyperprolactinemia, the availability of prolactin-sparing antipsychotics, and effective treatment, prolactin monitoring is emphasized, which will help with timely interventions. The UK’s National Institute for Health and Care Excellence suggests checking prolactin levels 6 months after initiating an antipsychotic drug and then every 12 months. Prolactin monitoring is not required for aripiprazole, clozapine, quetiapine, or olanzapine (< 20 mg/day) unless symptoms of hyperprolactinemia are present.³ Similarly, the American Psychiatric Association recommends screening for hyperprolactinemia symptoms at initial assessment, checking prolactin level if indicated based on clinical history, and screening again for hyperprolactinemia symptoms during follow-up. Prolactin levels should be checked in patients taking prolactin-raising antipsychotics at each visit until stable, and yearly thereafter (Table). The guidelines also state that if indicated by the clinical history at follow-up, the prolactin level should be checked.¹⁷ Further, the guidelines emphasize checking for symptoms of hyperprolactinemia during treatment with antipsychotics.

Managing Hyperprolactinemia in Psychiatric Patients

Common options in managing hyperprolactinemia related to antipsychotic use involve dose reduction or discontinuation of the antipsychotic drug, switching to a prolactin-sparing drug, or adding aripiprazole (range, 5-10 mg) as a partial dopamine agonist.^1,3,9 Addition of a full dopamine agonist (cabergoline, bromocriptine, and terguride) or metformin has also been reported to decrease prolactin levels,⁹ but more studies are required. When patients are well settled and symptoms are controlled with the antipsychotic, the approach of adding aripiprazole is usually preferred, which has a robust evidence base.^2,9 It is essential to inform patients about the clinical concerns of hyperprolactinemia and discuss the options.

In essence, the association of prolactin in patients with mental illnesses is far more complicated than simply the adverse effects of antipsychotics. There is a need for further exploration of the contribution of stress-related changes in prolactin levels in a range of psychiatric disorders.

Dr Kar is a consultant psychiatrist and college tutor at Black Country Healthcare NHS Foundation Trust in Wolverhampton, UK. He is also an honorary professor of psychiatry at the University of Wolverhampton.

References

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16. Miao X, Fu Z, Luo X, et al. A study on the correlations of PRL levels with anxiety, depression, sleep, and self-efficacy in patients with prolactinoma. Front Endocrinol (Lausanne). 2024;15:1369729.

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