Hyperprolactinaemia caused by antipsychotic drugs

For more than quarter of a century it has been recognised that traditional antipsychotic drugs, prescribed in therapeutic doses, can cause symptomatic hyperprolactinaemia.¹ Unlike the extrapyramidal side effects of these drugs, hyperprolactinaemia has attracted little clinical and scientific interest. This is despite the fact that it is common, causes distressing endocrine symptoms, and has potential long term complications. The widespread use of antipsychotic drugs in a variety of psychiatric conditions—including schizophrenia, bipolar disorder, psychotic depression, and anxiety disorders—and the recent introduction of prolactin sparing atypical antipsychotics make it timely to review this syndrome.

Antipsychotic drugs are thought to exert their therapeutic effect by an antidopaminergic action in the mesolimbic system, whereas their effect of raising prolactin is mediated by the blockade of dopamine D₂ receptors on pituitary lactotrophs. An early prospective but uncontrolled study found that several weeks of treatment with antipsychotic drugs increased mean prolactin concentrations over pretreatment values several-fold,² and this result has been confirmed in more recent prospective studies with and without control groups. Although a dose-response relation between prolactin concentrations and daily doses of conventional antipsychotics is likely, major increases in prolactin can occur with low doses.²,³ During long term treatment prolactin levels remain above normal in most cases. Serum concentrations return to normal within three weeks after patients stop oral treatment but may remain raised for six months after discontinuation of intramuscular depots.

Some of the new atypical antipsychotics, such as clozapine, quetiapine, and olanzapine, have no effects or only mild effects on serum prolactin, but others can cause sustained prolactin elevation across their dose range. Presumably this reflects differences in affinity to pituitary D₂ receptors and, possibly, regional selectivity.

Symptoms of hyperprolactinaemia result from the direct effects of prolactin on target tissues or the indirect effects of reduced gonadal hormone concentrations secondary to prolactin. Preliminary data suggest that some women with schizophrenia have a pre-existing hypo-oestrogenic state and may therefore be particularly sensitive to the effects of prolactin. Among women receiving traditional antipsychotics the most common symptoms are galactorrhoea and amenorrhoea or oligomenorrhoea, for which prevalence rates of 50% or more have been reported in cross sectional studies.⁴,⁵ However, a recent survey has highlighted that clinicians underestimate their prevalence.⁶ Explanations for this neglect include the lack of externally visible symptoms, reluctance of clinicians and patients to discuss potentially embarrassing complaints, and clinicians' lack of awareness in the area. Other symptoms of hyperprolactinaemia in women include vaginal dryness and atrophy, infertility, hirsutism, and acne.

Hyperprolactinaemia induced by antipsychotic drugs can present with breast changes in men, but these symptoms are relatively uncommon. The prevalence of sexual dysfunction in men and women treated with antipsychotic drugs is high;⁷ however, the contribution of hyperprolactinaemia and secondary hypogonadism needs to be determined. Other factors, including psychosocial aspects of the psychiatric illness and central and peripheral drug effects, may be more important in the aetiology of sexual dysfunction.

The long term consequences of gonadal hormone deficiency, secondary to raised prolactin, are a cause for concern. For example, findings in the general population raise the question of whether psychiatric patients with prolonged premenopausal oestrogen deficiency may not benefit from the protective effects of oestrogens on cognitive and cardiovascular function. Oestrogen deficiency before and after menopause is also an established risk factor for osteoporosis. Women and men with tumours that secrete prolactin have reduced bone densities at vulnerable sites.⁸,⁹ In men and women this loss of bone density has been shown to be caused by the gonadal dysfunction rather than the prolactin excess and to reverse fully or partially after treatment.

These findings are particularly relevant to patients with schizophrenia, given that they often begin antipsychotic treatment in their late teens and early twenties, before reaching the age of peak bone mass, and may continue treatment for years, if not indefinitely. Two small studies of psychiatric patients treated with antipsychotics with or without antidepressants reported reductions in bone mineral densities at sites vulnerable to fracture.¹⁰,¹¹ Risk factors other than hypogonadism for osteoporosis—most importantly, excessive alcohol intake and cigarette smoking—are, however, also common in these patients. An adequate trial is needed to assess the relative contribution of these variables to bone density and to compare patients treated with prolactin raising and prolactin sparing antipsychotics.

Because symptoms of hyperprolactinaemia often do not abate after the dose of antipsychotic drug is reduced, other management strategies are usually needed if the symptoms need treating. Dopamine agonists have been used to reverse hyperprolactinaemia but may exacerbate psychotic symptoms.¹² Hormone replacement can prevent the effects of oestrogen deficiency, but its risks include thromboembolism. Both these approaches are now less attractive, given the availability of prolactin sparing atypical antipsychotics.

The relative merits of traditional and atypical antipsychotics have been much discussed recently. Hyperprolactinaemia and its symptoms are, however, often absent from the debate. One considerable weakness in the literature is the lack of data from controlled prospective studies on the development of endocrine symptoms and on their possible long term consequences; another weakness is the studies' concentration on women.

Despite these shortcomings, current data are sufficient to influence clinical practice. Clinicians should manage antipsychotic treatment for individual patients, carefully weighing up not only the likely duration of treatment, efficacy, type of formulation, and costs but also the full range of side effects, the distress they cause, and the patient's preference. When patients are prescribed antipsychotics known to raise prolactin they should be informed about endocrine symptoms. The presence of endocrine symptoms should be assessed before treatment and monitored regularly thereafter.