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Antipsychotic-induced hyperprolactinaemia: case studies and review
  1. Shweta Mittal1,
  2. Suveera Prasad2,
  3. Adwaita Ghosh2
  1. 1 Consultant Psychiatrist, Department of Psychiatry, Bassetlaw Hospital, Nottinghamshire Healthcare NHS Foundation Trust, Worksop, UK
  2. 2 Consultant Psychiatrist, Adult Mental Health Inpatient Unit, Rotherham Doncaster and South Humber Mental Health NHS Foundation Trust, Doncaster, UK
  1. Correspondence to Dr Shweta Mittal, Consultant Psychiatrist, Department of Psychiatry, Bassetlaw Hospital, Worksop, S81 0BD, UK; doc_smittal{at}yahoo.co.uk

Abstract

Antipsychotics are a known cause of hyperprolactinaemia and can be associated with significant health issues in short term and long term. The effects vary with gender and age of the individual and can contribute towards non-concordance and hence relapse in mental health of our patients. Clinicians need to educate the patients about this significant side effect of not only antipsychotic medications but other medications causing hyperprolactinaemia commonly prescribed in primary care.

  • psychiatry
  • adult psychiatry

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Introduction

Hyperprolactinaemia is a known side effect of antipsychotic medications. High prolactin levels can hinder the physiological functioning of endocrine, reproductive and metabolic systems.1 Antipsychotic drugs are frequently used, not only in patients presenting with psychosis, but also as a mood stabiliser medication and to augment antidepressant and antianxiety effects of other psychotropic medications.2 First-generation antipsychotics are known to increase the incidence of hyperprolactinaemia in 40%–90% of patients.3 Among the second-generation antipsychotics, risperidone,4 amisulpride and paliperidone are referred to as prolactin-raising antipsychotics and aripiprazole as a prolactin-sparing antipsychotic.5

Symptoms due to hyperprolactinaemia are often under-reported as patients do not relate them to the use of antipsychotic drugs. Antipsychotic medications differ in their propensity to raise prolactin levels and symptoms depend on numerous factors including gender and age.6 Symptoms of hyperprolactinaemia are different in men and women.6 Men are likely to experience loss of libido and erectile dysfunction.7 Women are more likely to develop oligomenorrhoea and amenorrhoea. Both men and women can develop galactorrhoea and infertility. Drug-induced hyperprolactinaemia is seen slowly following commencement of medication. Prolactin levels tend to return back to normal 3 days after the medication is discontinued.8 9

Physiology of prolactin secretion and dopamine

Prolactin is a polypeptide hormone secreted mainly by the acidophilic lactotroph cells of anterior pituitary.10 Prolactin is also secreted by the mammary glands, placenta, lymphocytes and other parts of the brain. It also inhibits the effects of gonadotrophins.11 Prolactin secretion follows a circadian rhythm. Prolactin secretion is affected by a variety of factors both from the external environment, like stress and suckling, and internal environment like oestrogen from ovary.12

Hyperprolactinaemia is one of the most common endocrinological disorders of the hypothalamic–pituitary axis. There are several known causes of hyperprolactinaemia like sleep, pregnancy, stress and breast stimulation. The pathological causes include tumours, seizures, severe hypothyroidism, Cushing’s disease, acromegaly and herpes zoster. Commonly used drugs both in primary and secondary care causing hyperprolactinaemia other than antipsychotics include antidepressants—fluoxetine, sertraline, paroxetine, metoclopramide, domperidone, verapamil, cimetidine and ranitidine.3 13

Incidence and prevalence of hyperprolactinaemia

Nearly half of the patients receiving antipsychotic drugs develop hyperprolactinaemia.8 9 14 15 The reported prevalence of hyperprolactinaemia in people receiving the first-generation antipsychotics ranges from 33% to 87% depending on the dose.14 15 Amisulpride, risperidone and paliperidone are the second-generation antipsychotics with highest incidence of hyperprolactinaemia and can also cause sustained hyperprolactinaemia. Hyperprolactinaemia is also seen in order of incidence with olanzapine and quetiapine, negligible with clozapine and aripiprazole.14–17 Significant hyperprolactinaemia with first-generation antipsychotics, risperidone and amisulpride occurs within 14 days and peaks 1–2 months after treatment initiation.5 The women of childbearing age and adolescents are usually more susceptible to hyperprolactinaemia.

CASE vignettes

Over a 6-month period on a psychiatric inpatient unit in 2016, we encountered three patients with significantly raised prolactin levels attributed to antipsychotic medications.

Case history 1

A 71-year-old woman with bipolar disorder and on 600 mg lithium presented initially with renal failure. The lithium was stopped and risperidone was commenced at 0.5 mg and titrated to 1.5 mg over the next few days. Three weeks later she presented with itchiness, inversion and galactorrhoea of the left nipple. Prolactin level was 3457 mU/L. Subsequent prolactin level after 10 days was 2488 mU/L indicating the development of prolactin tolerance. Risperidone was changed to aripiprazole. Although the prolactin level returned to within normal range, the patient had two subsequent admissions to an inpatient psychiatric unit lasting 6 months in total due to a relapse of her bipolar illness. This case history illustrates risperidone-induced symptomatic hyperprolactinaemia.

Case history 2

A 61-year-old woman with treatment-resistant paranoid schizophrenia presented with exacerbation of her psychotic symptoms which were characterised by multiple persecutory delusions and auditory hallucinations, including beliefs that the fire brigade and police were coming out to her house. She was medicated with clozapine at a dose of 800 mg, aripiprazole 15 mg, depakote 1000 mg, metformin and senna. She also suffered from recurrent urinary tract infections, each of which resulted in exacerbation of her psychotic symptoms. She had limited insight into her symptoms. Her prolactin level was 169 mU/L (normal). Aripiprazole was replaced with amisulpride 400 mg and 3 days later, her prolactin level was 4035 mU/L. Subsequently it was noted to have remained in the range of 3545–4283 mU/L over the next 7 weeks. MRI of the pituitary with contrast was normal. ECG was normal. The patient showed a marked improvement in her psychotic symptoms and was discharged back to community. This case history shows how prolactin levels were significantly affected when aripiprazole was withdrawn and replaced by amisulpride.

Case history 3

A 30-year-old woman with known diagnosis of paranoid schizophrenia had raised prolactin in the range of 1135–3187 mU/L while she was on oral 2 mg BD and risperidone depot 37.5 mg fortnightly. She had six admissions in the last 4 years, most of them lasting for >8 weeks in the adult mental health inpatient unit. Interestingly, her previous prolactin level was normal while she was still on risperidone depot 37.5 mg fortnightly and oral risperidone 2 mg BD PRN. This case supports the results of a 5-year observational study which concluded that prolactin levels of 59 patients who remained on risperidone reduced significantly over time.17

Short-term and long-term consequences of hyperprolactinaemia among patients on antipsychotics

Symptoms of hyperprolactinaemia are different in men and women. In women, hyperprolactinaemia commonly presents with oligomenorrhoea or amenorrhoea, breast tenderness and galactorrhoea.18 19 On the other hand, men present with gynaecomastia and erectile dysfunction.5 Impaired libido is common in both genders. Study by Haeflinger in 2006 found amenorrhoea in three premenopausal women treated with risperidone.14 The symptoms are summarised in table 1. It is important to make inquires with the patients about symptoms of hyperprolactinaemia at regular intervals and record these in the patients’ notes.

Table 1

Symptoms of hyperprolactinaemia

Monitoring

Regular monitoring of serum prolactin before and during treatment helps identify those patients developing antipsychotic-induced hyperprolactinaemia.15 Ideally, all patients should have a baseline level of prolactin done before commencing antipsychotic medication.20 This is particularly useful as high prolactin level with initial normal baseline level confirms that hyperprolactinaemia was as a consequence of recently commenced antipsychotic medication.15 21 It is important to bear in mind that stress, exercise, physical discomfort and even the fear of having a blood test done can cause moderate increase in prolactin concentration.5 A blood test for prolactin levels should be done at least 1 hour after waking up in the morning.15 If the prolactin level is modestly high, it is worth repeating the test due to above factors frequently influencing the results. Antipsychotic medication can lead to an acute rise in prolactin levels and hence it is advised not to take the blood sample 2–4 hours post antipsychotic dosage.16

Drugs like clozapine, olanzapine, quetiapine, aripiprazole and ziprasidone do not normally increase the prolactin level above the normal range at standard doses and annual prolactin level is suffice. On the other hand, first-generation antipsychotic drugs and risperidone, paliperidone and amisulpride need regular 6 monthly monitoring and detailed history from the patient to enquire about above-mentioned symptoms. More recently, aripiprazole has been increasingly used as an adjuvant to reduce raised prolactin levels associated with other antipsychotics.15 22 23

Women with mildly raised prolactin levels (up to 1000 mU/L) having regular periods should be reassured and advised about the likelihood of the reduction in prolactin levels with time. Further detailed investigation is not warranted in such cases apart from repeat serum prolactin level at 3 monthly intervals to see change in prolactin levels.3 15 Monitoring and management of hyperprolactinaemia based on serum prolactin level is summarised in table 2.

Table 2

Monitoring and management of antipsychotic-induced hyperprolactinaemia

Asymptomatic patients with prolactin levels up to 2500 mU/L require close monitoring to look for emergence of any symptoms and to repeat prolactin levels every 3 months.3 Raised prolactin level associated with antipsychotics tends to return back to within the normal range 3 days after the medication is discontinued.8 9 If symptomatic, patients should have discussion with their treating psychiatrist about the option to either change the antipsychotic to a prolactin-sparing one or to reduce the dose of antipsychotic. If neither of these options is feasible, treating psychiatrist may consider low-dose aripiprazole as an adjuvant.22 23 Continue to monitor prolactin levels every 3 months until normalisation is achieved and annually thereafter.3

Patients with prolactin levels between 2500 and 5000 mU/L require close monitoring and further discussion with the treating psychiatrist regarding treatment options based on risk–benefit ratio.5

A prolactin level >5000 mU/L usually indicates a true prolactinoma and a referral to endocrinologist is warranted.5 24 MRI pituitary fossa is advised to rule out prolactinomas and interpret in conjunction with symptoms such as visual field defects. Consideration should be given to organising bone density scan if female patients present with amenorrhoea for >1 year assuming that antipsychotic-induced hyperprolactinaemia is the primary reason for amenorrhoea.5 Reliable and efficient urine human chorionic gonadotrophin test should be done to rule out pregnancy in all patients presenting with amenorrhoea if they are in a relationship and are of a reproductive age.

Management of antipsychotic-induced hyperprolactinaemia

Management should be tailored to the individual patient taking into account serum prolactin levels, development of tolerance, duration of psychosis, efficacy of antipsychotics used previously by the patient, gender and so on. If hyperprolactinaemia persists, consider lowering the dose of the drug or changing to another antipsychotic medication. Antipsychotics not usually associated with hyperprolactinaemia are aripiprazole, clozapine, quetiapine and olanzapine.5 15 If this is not possible due to the risk of psychotic relapse then adjunctive treatment with aripiprazole at the dose of 5 mg/day should be considered.15 25 26 Different treatment options are presented in tabulated form in box 1. Other options include prescribing a dopamine receptor agonist3 27 28 or prescribing oestrogen replacement in hypo-oestrogenic female patients. Further research is needed to establish the efficacy and risks of last two treatment options.5

Box 1

Treatment options for antipsychotic-induced hyperprolactinaemia

  •  Stop or reduce the dose of medication.3 5 15

  •  Change to prolactin-sparing drug.3 5 15

  •  Add aripiprazole.15 25 26

  •  Add dopamine agonist.3 5 15

  •  Oestrogen replacement in women.3

Conclusion

Hyperprolactinaemia is a known but often under-recognised as a side effect of antipsychotic medication.15 Evidence is emerging to show that persistent asymptomatic hyperprolactinaemia can be associated with osteoporosis or possibly breast cancer in the long term.5 29 Patients might not correlate the side effects with commencement of antipsychotic medication.5 Clinicians often underestimate the prevalence of patients’ symptoms secondary to hyperprolactinaemia.30 It is vital that treating psychiatrist, mental health team and other clinicians make patient aware of the potential symptoms of hyperprolactinaemia and review this at regular intervals.

Main messages

  • Hyperprolactinaemia is a known but often under-recognised as a side effect of both psychotropic and non-psychotropic medication.

  • Regular monitoring of serum prolactin before and during treatment helps identify those patients developing drug-induced hyperprolactinaemia.

  • Clinicians need to be mindful of both physiological and pathological causes of hyperprolactinaemia.

Current research questions

  • Is persistent asymptomatic hyperprolactinaemia detrimental to physical health of our patients?

  • Is it safe to prescribe a dopamine receptor agonist or oestrogen replacement in hypo-oestrogenic female patients with hyperprolactinaemia?

  • Is hyperprolactinaemia the most common reason for discontinuation of antipsychotic medication?

Key references

  • Haddad PM, Wieck A. Anti-psychotic-induced hyperprolactinaemia mechanisms, clinical features and management. Drugs 2004;64:2291–314.

  • Holt RI, Peveler RC. Anti-psychotics and hyperprolactinaemia: Mechanisms, consequences and management. Clin Endocrinol 2011;74:141–147.

  • Bostwick JR, Guthrie SK, Ellingrod VL. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy 2009;29:64–73.

  • Gupta S, et al. Management of antipsychotic-induced hyperprolactinaemia. BJPsych Adv 2017; 23:278–286.

  • Torre DL, Falorni A. Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag 2007;3:929–951.

Self-assessment questions

  1. Which of the following is prolactin-sparing antipsychotic?

    1. Risperidone

    2. Haloperidol

    3. Amisulpride

    4. Aripiprazole

  2. Which of the following is NOT a short-term side effect of antipsychotic-induced hyperprolactinaemia?

    1. Erectile dysfunction

    2. Breast tenderness

    3. Osteoporosis

    4. Acne

  3. Prolactin secretion can be influenced by

    1. Stress

    2. Seizures

    3. Time of the day

    4. All of the above

    5. None of the above

  4. Augmentation with risperidone is an appropriate management plan for a patient with symptomatic hyperprolactinaemia with prolactin level above 2500 mU/L: True or False?

  5. Ranitidine can cause hyperprolactinaemia: True or False?

Answers

  1. d) Aripiprazole

  2. c) Osteoporosis

  3. d) All of the above

  4. False

  5. True

Acknowledgments

The authors are thankful to the three patients who allowed them to publish their case vignettes.

References

Footnotes

  • Contributors All authors: played equal role in preparation of this manuscript; did literature search and wrote the article. SP: came up with the idea of review article on anti-psychotic induced hyperprolactinaemia due to lack of clear guidelines about monitoring and management of high prolactin. SM: is the guarantor. AG: significantly contributed and wrote about the physiology of prolactin.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement This article was presented as a poster presentation in Royal College of Psychiatry International Congress in Edinburgh in June 2017.