Angelika Wieck

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

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.

Increased sensitivity of dopamine receptors and recurrence of affective psychosis after childbirth.

OBJECTIVE--To test the hypothesis that affective psychosis after childbirth is associated with an altered sensitivity to dopaminergic stimulation. DESIGN--Prospective study of pregnant women at high risk of developing an affective psychosis after childbirth. Clinical assessments in pregnancy and after delivery were made by using a semistructured interview (schedule for affective disorders and schizophrenia) and psychiatric illnesses were categorised according to operational criteria (research diagnostic criteria). SETTING--Obstetric and psychiatric departments in and around Greater London. SUBJECTS--29 pregnant women with a history of bipolar or schizoaffective psychosis and 47 control pregnant women. Of these, 16 from each group participated in a growth hormone challenge test and the results for 15 women in each group were analysed. INTERVENTIONS--On the fourth day postpartum women participating in the hormone challenge test were given a subcutaneous injection of a small dose (0.005 mg/kg) of the dopamine agonist apomorphine. MAIN OUTCOME MEASURES--Growth hormone secretion in response to apomorphine as an index of the functional state of hypothalamic dopamine receptors. RESULTS--Eight of the 15 women at risk of psychosis subsequently had a recurrence of illness (five bipolar, one schizomanic, and two major depressive illnesses); these women had significantly greater growth hormone responses to apomorphine than the seven at risk women who remained well and the 15 controls, and there were no significant differences between groups in average baseline growth hormone concentrations. The mean (SD) concentrations for women with recurrence, women at risk who remained well, and control women respectively were: average baseline concentrations 1.06 (1.14), 1.44 (1.39), and 0.90 (1.34) mU/l; peak increase in concentrations 13.68 (12.95), 3.46 (4.68), and 3.40 (3.83) mU/l (between group difference p less than 0.05); average increase in concentrations 6.74 (7.01), 1.78 (3.39), and 1.40 (2.05) mU/l (p less than 0.05). CONCLUSIONS--The onset of affective psychosis after childbirth was associated with increased sensitivity of dopamine receptors in the hypothalamus and possibly elsewhere in the brain. Such changes may be triggered by the sharp fall in circulating oestrogen concentrations after delivery.

A review of valproate in psychiatric practice

Valproate (2-propylpentanoate) is available as valproic acid, sodium valproate and semisodium valproate. It has actions on dopamine, GABA and glutamate neurotransmission and intracellular signaling. Its main psychiatric use is to treat bipolar disorder. It has been used in other psychiatric disorders, including schizophrenia and borderline personality disorder, but data are insufficient to recommend this. In acute mania, valproate monotherapy has similar efficacy to antipsychotic drugs and lithium whereas the combination of valproate and an antipsychotic is more effective than either drug alone. In maintenance treatment of bipolar disorder, valproate monotherapy has comparable efficacy to olanzapine although placebo-controlled evidence is limited. Maintenance treatment with valproate and quetiapine or olanzapine is more efficacious than valproate alone when an acute episode responds to the combination. Common adverse effects of valproate include weight gain, gastrointestinal symptoms, sedation, tremor and mild elevation of hepatic enzymes. Serious hepatic toxicity is rare in adults. Many adverse effects are dose related and resolve with dose reduction. Valproate is teratogenic and specifically associated with neural tube defect. Preliminary evidence has linked in utero exposure to decreased verbal intelligence in the offspring. These effects, plus a probable increased risk of polycystic ovary syndrome, limit valproates use in women of childbearing potential.

An evaluation of two bonding questionnaires: a comparison of the Mother-to-Infant Bonding Scale with the Postpartum Bonding Questionnaire in a sample of primiparous mothers

SummaryThe emotions and attitudes of mothers towards their infants are crucial for the child’s well-being and development. Some mothers experience a delay in the onset of maternal affection after childbirth and occasionally a longer lasting failure to bond will ensue. Little is known about the precise prevalence of these difficulties, how they relate to maternal mental health, how they develop over time and what their biological and psychosocial correlates are. In research studies the mother-infant relationship has traditionally been assessed using observational methods but these are time consuming and not suited for screening in clinical practice. Two self-rating instruments have recently been developed to assess maternal bonding. Both can be used in large samples of recently delivered mothers including those suspected to be at high risk of bonding disorders. In this study, the psychometric properties of the 8-item Mother-to-Infant Bonding Scale (MIB) and the 25-item screening questionnaire for mother–infant bonding disorders, namely the Postpartum Bonding Questionnaire (PBQ), were examined in a sample of first-time mothers in order to establish their reliability and validity. Ninety-six women completed the MIB, PBQ and the Kennerley Blues Scale on day 2–4 postpartum. Both bonding instruments demonstrated acceptable reliability and reasonable validity, with the exception of the PBQ subscale of risk of abuse.

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 …

Neonatal symptoms following maternal paroxetine treatment : Serotonin toxicity or paroxetine discontinuation syndrome?

We report a case of neonatal symptoms of irritability, increased tonus and convulsions after in-utero exposure to paroxetine 30mg/day. The infant’s symptoms commenced on the first day after birth and persisted for 10 days. Paroxetine levels were undetectable on day 6. Extensive investigations excluded infective and metabolic causes. Serotonin toxicity due to paroxetine seems the most likely mechanism, though an important differential diagnosis is a paroxetine discontinuation (withdrawal) syndrome. Differentiating between these two syndromes in the neonate presents a dilemma for clinicians. Irrespective of the mechanism, we recommend that all neonates exposed to antidepressants, particularly serotonin reuptake inhibitors (SSRIs), during the last trimester should be followed-up closely for adverse symptoms commencing in the first 10 days after birth. The possibility of such symptoms needs to be discussed with women who are considering starting or continuing antidepressant treatment in pregnancy. All neonatal adverse drug events should be reported to a pharmacovigilance centre. Further research is warranted.

Antipsychotic induced hyperprolactinaemia: a series of illustrative case reports

Hyperprolactinaemia is a common side-effect of many antipsychotic drugs but, in comparison to extrapyramidal side-effects, it has received little attention. Four case reports are presented which illustrate important clinical and pharmacological aspects of the syndrome. Two of the cases were caused by conventional antipsychotic drugs and two by risperidone, an atypical antipsychotic. Symptoms included gynaecomastia, galactorrhoea, amenorrhoea and sexual dysfunction. Three patients were switched to a prolactin sparing antipsychotic leading to normalization of serum prolactin and resolution of the symptoms. Patients prescribed prolactin elevating antipsychotics should, where possible, have this issue explained to them prior to commencing treatment and be screened for symptoms suggestive of hyperprolactinaemia before starting treatment and regularly thereafter.

Menstrual Cycle Effects on Hypothalamic Dopamine Receptor Function in Women with a History of Puerperal Bipolar Disorder

Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder.

An examination of the psychometric properties and factor structure of the Post‐partum Bonding Questionnaire in a clinical inpatient sample

OBJECTIVE To examine the factor structure and psychometric properties of the Post-partum Bonding Questionnaire (PBQ) in a sample of psychiatric inpatients. METHODS One hundred and thirty-two women who were admitted to a Mother and Baby Unit for psychiatric inpatient treatment completed the PBQ and the Beck Depression Inventory (BDI-II). The factor structure of the PBQ was examined using confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) techniques. RESULTS The original four-factor structure of the PBQ was not replicated by CFA and EFA in this sample. A three-factor solution was identified as the most stable and clinically meaningful solution. Factors pertaining to impaired bonding, anxiety and irritability, and anxiety about child care responsibilities were identified in the CFA but were not entirely replicated in the EFA. The internal consistencies of the three subscales were also acceptable. PBQ scores were also significantly associated with depression scores. CONCLUSION The findings suggest that the original four factors of the PBQ should be used with caution. Items pertaining to risk of abuse had to be omitted alongside one other item, resulting in a 22-item solution. Further psychometric evaluation of this scale is recommended.

A satisfaction survey of women admitted to a Psychiatric Mother and Baby Unit in the northwest of England

SummaryA Satisfaction Questionnaire for an Inpatient Mother and Baby Unit was developed covering general psychiatric and specific perinatal aspects of the service. In a study of 41 women admitted over one year twenty returned the completed questionnaire. Among respondents overall satisfaction with the service was very high and women preferred it to a general psychiatric ward. Respondents were most dissatisfied with degree of involvement in the planning and the level of decision making about their care which is a recurring theme in surveys of psychiatric inpatients.