The Dopamine Hypothesis of Schizophrenia: A Review*

Hyperprolactinaemia is an important but neglected adverse effect of antipsychotic medication. It occurs frequently with conventional antipsychotics and some atypical antipsychotics (risperidone and amisulpride) but is rare with other atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, ziprasidone). For this reason the terms 'prolactin-sparing' and 'prolactin-raising' are more useful than 'atypical' and 'conventional' when considering the effect of antipsychotic drugs on serum prolactin. During antipsychotic treatment prolactin levels can rise 10-fold or more above pretreatment values. In a recent study approximately 60% of women and 40% of men treated with a prolactin-raising antipsychotic had a prolactin level above the upper limit of the normal range. The distinction between asymptomatic and symptomatic hyperprolactinaemia is important but is often not made in the literature. Some symptoms of hyperprolactinaemia result from a direct effect of prolactin on target tissues but others result from hypogonadism caused by prolactin disrupting the normal functioning of the hypothalamic-pituitary-gonadal axis. Symptoms of hyperprolactinaemia include gynaecomastia, galactorrhoea, sexual dysfunction, infertility, oligomenorrhoea and amenorrhoea. These symptoms are little researched in psychiatric patients. Existing data suggest that they are common but that clinicians underestimate their prevalence. For example, well conducted studies of women treated with conventional antipsychotics have reported prevalence rates of approximately 45% for oligomenorrhoea/amenorrhoea and 19% for galactorrhoea. An illness-related under-function of the hypothalamic-pituitary-gonadal axis in female patients with schizophrenia may also contribute to menstrual irregularities. Long-term consequences of antipsychotic-related hypogonadism require further research but are likely and include premature bone loss in men and women. There are conflicting data on whether hyperprolactinaemia is associated with an increased risk of breast cancer in women. In patients prescribed antipsychotics who have biochemically confirmed hyperprolactinaemia it is important to exclude other causes of prolactin elevation, in particular tumours in the hypothalamic-pituitary area. If a patient has been amenorrhoeic for 1 year or more, investigations should include bone mineral density measurements. Management should be tailored to the individual patient. Options include reducing the dose of the antipsychotic, switching to a prolactin-sparing agent, prescribing a dopamine receptor agonist and prescribing estrogen replacement in hypoestrogenic female patients. The efficacy and risks of the last two treatment options have not been systematically examined. Antipsychotic-induced hyperprolactinaemia should become a focus of interest in the drug treatment of psychiatric patients, particularly given the recent introduction of prolactin-sparing antipsychotics. Appropriate investigations and effective management should reduce the burden of adverse effects and prevent long-term consequences.

Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management.

Long-term administration of typical and atypical antipsychotic drugs (AP) induces excessive weight gain which afflicts up to 50% of patients, impairs health and interferes with treatment compliance. Basic and clinical research has shown that AP may affect body weight through diverse mechanisms. Increased appetite is probably related to the interaction of AP with neuronal receptors to dopamine, serotonin and histamine. Additional metabolic-endocrine disruption of weight regulation may be related to the effects of AP-induced hyperprolactinaemia on gonadal-adrenal steroids and insulin sensitivity. In humans, programmed physical activity, dietary restriction, anorectic agents, and drugs that counteract hyperprolactinaemia have been shown to be successful in a limited number of studies. Two novel strategies could expand the available therapeutic options. First, in preclinical experiments in female rats the estradiol antagonist/agonist drug tamoxifen or estradiol itself have been shown to completely prevent the obesity provoked by the AP sulpiride, and to induce an endocrine-metabolic milieu that seems to counteract AP-induced obesity. Secondly, it has also been shown that oral antihyperglycaemic agents such as metformin may decrease body weight and counteract insulin resistance and hyperinsulinaemia which is correlated with several metabolic abnormalities in obese subjects. Lastly, estradiol replacement, tamoxifen and/or antihyperglycaemic agents are not devoid of significant side-effects, and these drugs have not been tested in obese psychiatric patients. Therefore, further research is needed before their clinical use may be recommended.

Body weight gain induced by antipsychotic drugs: mechanisms and management.

• Serum prolactin levels were studied before and during longterm administration of phenothiazines on a twice daily schedule to 27 newly admitted schizophrenic patients. An increase in serum prolactin is believed to be a reflection of inhibition of dopamine receptors in the hypothalamopituitary axis. By 72 hours after the initiation of treatment, all 27 patients had persistently elevated serum prolactin levels averaging 3.2-fold and 3.8-fold in men and women, respectively. There was a lag between clinical response and dopamine blockade, as indicated by serum prolactin levels in most patients. Serum prolactin levels remained elevated during the one- to three-month period subjects were studied, suggesting there was no tolerance to this effect of phenothiazines. Serum prolactin levels tended to be higher with thioridazine than on equivalent doses of chlorpromazine or trifluoperazine hydrochloride. There was some evidence that the magnitude of the serum prolactin elevation correlated with clinical response. After cessation of phenothiazines, serum prolactin levels rapidly reverted to normal within 48 to 96 hours.

The effect of neuroleptics on serum prolactin in schizophrenic patients.

Using epidemiologic data, in an earlier study we formulated the hypothesis that estrogens can delay the onset of schizophrenia in females by raising the vulnerability threshold for this disease In animal experiments, Hafner and colleagues found evidence that chronic estradiol treatment reduces the sensitivity of dopamine (D2) receptors in the brain In the clinical study presented in this article, as a further step we examined the antipsychotic properties of estradiol in human females by testing whether schizophrenic symptomatology varies with estradiol serum levels

Can estradiol modulate schizophrenic symptomatology

Fifteen female psychiatric patients developed inappropriate breast activity and/or amenorrhoea while receiving treatment with phenothiazines and related drugs. In the majority plasma prolactin was clearly elevated. In those whose menstruation had not been affected, circulating levels of luteinizing hormone (LH), immunoreactive oestrogens (oestradiol) and progesterone followed the normal pattern of the menstrual cycle. In amenorrhoeic subjects, basal LH values were variable, mid-cycle peaks were absent, and oestrogen and progesterone levels were similar to values reported during the follicular phase of a normal cycle.

Medication was withdrawn subsequently from four patients. Breast secretion diminished and plasma prolactin fell to within the normal range, rising again when the drugs were reinstated. In two of three amenorrhoeic patients, withdrawal of medication led to a resumption of menstruation with a normal cyclical pattern of LH, oestrogens and progesterone.

The effects of phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea.

There is ample evidence that high doses of phenothiazines and other neuroleptics depress the pituitary-gonadal axis in experimental animals (De Wied, 1967), but the effects of these drugs on sex hormones in human subjects are still controversial (Shader and Di Mascio, 1970). Literature concerning growth hormone (GH) is even more controversial, since phenothiazines have been found to inhibit GH release in rodents (Muller et al., 1967) but to increase it in the rhesus monkey (Meyer and Knobil, 1967). In human subjects phenothiazines have been reported to depress both basal levels of GH and the response to hypoglycaemia (Sherman et al., 1971), while others have found that this response is enhanced (Schimmelbusch, Mueller and Scheps, 1971). Studies of prolactin levels are more consistent, showing raised prolactin both in experimental animals and in human subjects following administration of phenothiazines (Apostolakis et al., 1972; Hwang et al., 1971; Kleinberg et al., 1971; Sulman, 1970).

P. J. V. Beumont

Papers

The effects of phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea.

The effects of phenothiazines on endocrine function: II. Effects in men and post-menopausal women.

Some endocrine effects of phenothiazines: a preliminary report.