Prolactin monitoring for patients on antipsychotic drugs: A narrative review of clinical relevance

Search strategy

In a narrative review, we searched electronic databases, including PubMed and Google Scholar, and conducted additional manual searches of the bibliography. The searches were conducted in April 2025. The keywords included “hyperprolactinemia,” “causes,” “antipsychotic drugs,” “monitoring,” and “guidelines.”

Inclusion and exclusion criteria for studies

We included articles and guidelines that described hyperprolactinemia in the context of psychiatric patients, specific to its monitoring and management, in the context of antipsychotic drug-induced hyperprolactinemia. Articles published only in the English language up to April 2025 were considered. Recent articles and guidelines were prioritized over older ones on similar topics. Studies that described the investigation and management of hyperprolactinemia in physical illnesses were excluded. The papers selected varied in range, considering the specific topics covered, and involved observations, reviews, and recommendations.

Synthesis and presentation

The findings of the review were described narratively. The results were described under various areas such as causes, symptoms, clinical implications, investigations, treatment, and monitoring requirements as relevant to psychiatric practices. Based on this narrative review, current gaps in practices are highlighted, and recommendations for use in clinical practice while prescribing antipsychotic drugs are provided, along with a flow diagram for the decision-making process.

Causes of hyperprolactinemia

Prolactin may increase in specific physiological and pathological states or can be drug-induced. The causes of hyperprolactinemia are given in Table 1. In addition to all these, hyperprolactinemia can be idiopathic. In pregnancy, prolactin levels can rise to 10 times the normal range. Prolactinoma is a benign tumor of lactotrophs, and prolactin level can increase mildly to almost 50,000 ng/mL.

Mechanism of hyperprolactinemia

Prolactin secretion is controlled by the hypothalamus, which is mostly inhibitory through the prolactin factor.^[6] Dopamine inhibits prolactin secretion through type 2 receptors located on the lactotrophs. Prolactin-releasing factors are endothelial growth factor, dopamine antagonists, thyrotropin-releasing hormone, and vasoactive intestinal peptide. As dopamine inhibits prolactin secretion, dopamine antagonists such as antipsychotic drugs increase prolactin levels.

Prolactin level in psychosis

It has been reported that unmedicated women with schizophrenia and remitted patients who relapse have lower prolactin levels, suggesting a hyperdopaminergic state.^[6] The likelihood of clinical response to antipsychotic drugs is increased when the dopamine occupancy exceeds 65%; however, for hyperprolactinemia is at 72% or more.^[7] Prolactin response does not usually correlate with clinical response. However, baseline prolactin levels have been used to predict therapeutic response to risperidone.^[6] Interestingly, at a similar dosage, chronic neuroleptic therapy in women was associated with comparatively lower prolactin levels than acute administration; however, in men, there was no such difference.^[8]

It is essential to highlight that patients with first-episode psychosis may report symptoms of sexual dysfunction, which is common, with normal serum prolactin levels.^[9] Raised serum prolactin levels are thought to proportionally impede cognitive function and processing speed in both men and women with severe, enduring mental illness.^[10,11]

Antipsychotic induced hyperprolactinemia

Various factors are reported to influence antipsychotic-induced hyperprolactinemia. Patient-related factors include female sex,^[6] adolescence,^[12] reproductive age, and middle age;^[13] older age is associated with lower prolactin levels in women, but not in men.^[14] There are reports that men outnumber women in risperidone, haloperidol, and amisulpride-induced hyperprolactinemia.^[13] Patients who present with stress, are on antidepressants, buspirone, or have overt or subclinical hypothyroidism are at higher risk too.^[6] The subtype of psychosis and the duration of the psychotic symptoms contribute to the risk; lower risk is seen in individuals who have had psychosis for over 10 years and those taking prolactin-sparing antipsychotics.^[6]

The type of antipsychotic medications contributes, as they have differing potencies of inducing hyperprolactinemia. First-generation antipsychotic drugs such as haloperidol, chlorpromazine, and sulpiride are associated with increased prolactin.^[15,16] Among the second-generation antipsychotic drugs, amisulpride, risperidone, and paliperidone cause a considerable increase in serum prolactin.^[16] Based on the risk, the order of the top five antipsychotic drugs is risperidone, amisulpride, paliperidone, fluphenazine, and haloperidol.^[13] Asenapine, clozapine, quetiapine, and olanzapine are less frequently associated with hyperprolactinemia, and aripiprazole decreases the level.^[2,17] Similarly, higher doses of antipsychotic drugs have been associated with hyperprolactinemia,^[18] suggesting decreasing the dose as an option for managing antipsychotic induced hyperprolactinemia.^[15,19]

Antidepressant drugs and hyperprolactinemia

Some antidepressants, including selective serotonin reuptake inhibitors, can be associated with hyperprolactinemia, which is usually minimal and does not have much clinical significance.^[1,2] Routine serum prolactin testing is not recommended.^[2]

Symptoms of hyperprolactinemia

Hyperprolactinemia may remain asymptomatic in many patients for a long period; however, various signs and symptoms have been associated with it [Table 2].^[1,2,6,17] Most women with hyperprolactinemia do not have galactorrhea.^[1]

Clinical implications

As the symptoms suggest, hyperprolactinemia may have various long-term implications [Table 2]. It leads to bone mineral density loss,^[18] more specifically when associated with untreated amenorrhea in women or testosterone deficiency in men.^[20] If there is a mass effect, secondary to tumors, visual deficits, blindness, cranial nerve palsies, and pituitary apoplexy can occur. Complications related to hypopituitarism have been discussed.^[1]

Current evidence is suggestive of a link between hyperprolactinemia and breast cancer. The risk of breast cancer increases with the use of prolactin-raising antipsychotic drugs, compared to antipsychotic usage for 5 or more years, and to the use of any antipsychotic.^[21] It has been suggested to treat persons with a high risk of developing breast cancer and patients with a breast cancer history using a prolactin-sparing antipsychotic.^[2] In this regard, personal and family history of breast cancer should be ascertained.^[2] It has been suggested to provide information about the increased risk, monitor the prolactin levels, and screen for breast cancer in these patients.^[21] There are also suggestions of increased risk of reduced glucose tolerance, hyperinsulinemia, prostate cancer, and thromboembolic events.^[2]

Investigations

Serum prolactin level is best sampled with a mid-morning fasting sample, as prolactin levels usually peak between 4 am and 7 am. While it is reported that food has minimal effect on prolactin,^[1] some observed variations are linked to body mass index.^[22] It is suggested that fasting is not always essential; however, it is preferable when the initial value shows mild elevation.^[1]

In addition to serum prolactin, renal and thyroid function, insulin-like growth factor-1, luteinizing hormone, adrenocorticotrophic hormone, follicle-stimulating hormone, testosterone/estradiol, and beta HCG are usually considered to explore the associated probable causes.

Imaging through magnetic resonance imaging (MRI) or computed tomography scans of the pituitary fossa can help identify tumors; MRI being the preferred method. For high prolactin levels such as >140 ng/mL, MRI is recommended, particularly with symptoms suggestive of raised intracranial pressure (headache, visual field disturbance), and when antipsychotic medication is not easily attributable as the cause.^[2]

Assessment of bone density should be considered an integral component of chronic psychiatric disorder management, as many medications may adversely affect bone metabolism and significant morbidities associated with low bone density.^[20]

Prolactinoma and other pituitary tumors adjacent to the optic chiasma may compress it, leading to visual field defects such as bitemporal hemianopia. Visual field testing should be considered for these tumors.^[23]

Treatment

Treatment is focused on managing the cause^.[1] Pathological and drug-induced hyperprolactinemia requires specific interventions, which would include medications to lower prolactin levels, to reduce the size of the tumor, surgery to remove the tumor, radiation therapy, etc. In this article, treatment specific to psychiatric drug-induced hyperprolactinemia is discussed. It is suggested that the treatment is only indicated if there is osteoporosis, hypogonadism, or problematic galactorrhea.^[20]

The treatment options for psychiatric drug-induced hyperprolactinemia include reducing the dose or discontinuation of the suspected drug if possible, switching to a different drug with lesser effect on prolactin, the addition of a partial (e.g., aripiprazole) or full dopamine agonist drug, along with the suggestion of adding metformin.^[4] There is some evidence that switching from long-acting risperidone to paliperidone depot can reduce both sexual dysfunction symptoms and serum prolactin levels.^[24]

Aripiprazole is a safe and effective adjunctive medication that brings down the prolactin level, and it has a fair evidence base^[25] and has been suggested to be the first option.^[26] Similarly, adjunctive cabergoline and bromocriptine (full agonist) can decrease prolactin and have been suggested, including herbal remedies (shakuyakukanzo-to, chamomile, and Peony-Glycyrrhiza decoction).^[27] However, the adverse effects of these adjunctive drugs need to be kept in mind. A network meta-analysis found that switching to aripiprazole and adjunctive vitamin B6 has also been associated with a decrease in antipsychotic-induced hyperprolactinemia.^[25] Antipsychotic drugs with low affinity for D2 receptors, such as olanzapine, are an alternative.^[12]

Dopamine agonist therapy is not advisable when antipsychotic-induced hyperprolactinemia results in amenorrhea in females or testosterone deficiency in males. Hormone-replacement therapy, supplementing or replacing progesterone and estrogen in women and testosterone in men, is suggested, which may allow the continuation of the successful psychiatric treatment regimens without interruption.^[28] These hormonal treatments should be done by endocrinologists or appropriate specialists.^[2]

If the prolactin level does not normalize, and the levels remain high, further investigations are warranted, such as an MRI. This would need a referral to endocrinology. The clinical guidelines of the Endocrine Society suggest prolactin monitoring in symptomatic patients and in pathological states, but do not comment on prolactin-raising medications.^[17]

Monitoring requirements in psychiatry

Considering the side effects, many psychiatric medications need regular monitoring, which includes clozapine^[29,30] and other antipsychotics, lithium, etc. Routine prolactin monitoring for all patients taking antipsychotic drugs is not mandatory. In the usual clinical practice, serum prolactin is not measured unless the patient has hyperprolactinemia symptoms.^[17] However, undetected hyperprolactinemia may lead to complications over time. In addition, there are inconsistencies and controversies about routine prolactin monitoring,^[31] especially in asymptomatic cases.

In the UK guidelines for psychosis, schizophrenia, and bipolar disorder, the National Institute for Health and Care Excellence (NICE) recommends that prolactin should be measured 6 months after starting antipsychotic treatment and then annually. The importance of screening for hyperprolactinemia symptoms such as sexual dysfunction, low libido, and galactorrhea in both sexes, gynecomastia in men, and menstrual abnormalities in women. The NICE recommends that prolactin monitoring is not required for olanzapine (if daily dose <20 mg), clozapine, aripiprazole, or quetiapine.^[32,33]

The American Psychiatric Association guideline suggests screening for symptoms of hyperprolactinemia at initial assessment, checking prolactin level if indicated based on clinical history, and screening again for symptoms of hyperprolactinemia during follow-up. Prolactin level should be checked at each visit until stable and yearly thereafter if taking a known prolactin-raising antipsychotic. Prolactin level should be checked in follow-up at any point if indicated by the clinical history.^[34]

The Spanish consensus on the management of antipsychotic drug-related hyperprolactinemia suggests that prolactin levels over 50 ng/mL or with clinical symptoms require clinical intervention, which includes changes in antipsychotic prescribing (lowering doses, changing the antipsychotic drug, adding medication such as aripiprazole, which is known to reduce prolactin levels). In severe cases, where serum prolactin is over 100 ng/mL, it is recommended to intervene even if hyperprolactinemia symptoms cannot be identified, to address the longer-term risks of breast and endometrial cancer, osteoporosis, and cardiovascular complications.^[35]

In Brazil, the guideline suggests that in case of possible medication-induced hyperprolactinemia, the drug should be discontinued for 3 days and the prolactin level repeated. If short-term discontinuation is not possible, and with persistent doubt about the etiology, pituitary imaging is recommended.^[36]

As observed from the above guidelines of different countries, there are variations in prolactin monitoring,^[2] from a defined monitoring duration to symptom-linked monitoring. However, there appears to be consensus about clinical assessment of hyperprolactinemia symptoms and to check for prolactin level if there are symptoms. Most guidelines recommend screening for differential diagnoses and to discontinue or switch prolactin-raising agents.^[37] There are suggestions that serum prolactin level should be taken at baseline^[37] and at least one repeat measurement when a new antipsychotic medication is started.^[38] However, baseline monitoring before the antipsychotic drug initiation may not be possible even in the most ideal situations.

Many countries do not have specific prolactin monitoring requirements for psychiatric patients, and even if there are guidelines available in some countries, adherence to those does not appear adequate^[5] and is not a standard clinical practice.^[17] In addition, there are many areas of uncertainty, such as monitoring baseline prolactin, how to address increased baseline prolactin, long-term effects of antipsychotics on prolactin levels, specific risks of prolactinoma, breast cancer, etc. Hyperprolactinemia-related side effects also affect adherence to medications, with related consequences.

Considering the current evidence base, some general recommendations can be made for psychiatric practice and conducting clinical audits [Table 3]. The clinical decision pathway for choosing appropriate antipsychotic drugs, assessing, and managing hyperprolactinemia is given in Figure 1. There is a need for more research, gender-specific guidelines for management, monitoring of asymptomatic hyperprolactinemia, and fertility considerations.^[37]

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Figure 1:

Decision tree for clinical pathway assessing and managing hyperprolactinemia associated with antipsychotic drugs.

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