The Sexual Side-Effects of Antipsychotics

Neuroleptics or antipsychotics are prescribed for bipolar disorder and schizophrenia. They are used to treat a variety of psychiatric problems, such as preoccupation with troublesome and recurring thoughts, overactivity, and unpleasant and unusual experiences such as hearing and seeing things not normally seen or heard.

Some of the benefits of these antipsychotics may occur in the first few days, but it is not unusual for it to take several weeks or months to see the full benefits. In contrast, many of the side effects are worse when you first start taking it.

Antipsychotics, Prolactin and Sexual Side Effects

Antipsychotics can cause a raising of the body's level of a hormone called prolactin. In women, this can lead to an increase in breast size and irregular periods. In men, it can lead to impotence and the development of breasts. Most of the typical antipsychotic drugs, risperidone (Risperidal) and amisulpride have the worst effect.

The best-known function of prolactin is the stimulation and maintenance of lactation, but it has also been found to be involved in over 300 separate functions including involvement in water and electrolyte balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction and immunoregulation.

In humans, prolactin is also thought to play a role in the regulation of sexual activity and behavior. It has been observed that orgasms cause a large and sustained (60 min) increase in plasma prolactin in both men and women, which is associated with decreased sexual arousal and function. Furthermore, increased prolactin is thought to promote behaviors that encourage long-term partnership.

Studies of patients who are treatment-naive or who have been withdrawn from treatment for a period of time indicate that schizophrenia per se does not affect prolactin concentrations.

Sexual Problems Among Worst Side Effects

Patients with Schizophrenia and Bipolar Disorder consider sexual dysfunction to be among the most important side effects. Sexual dysfunction includes low sexual desire, difficulty maintaining an erection (for men), difficulty achieving orgasm.

(If you have any of these symptoms and they are causing you concern, contact your doctor. He/she may be able to reduce your dose or change your medication.)

These adverse antipsychotic sexual side effects can have a serious negative impact on the patient in terms of causing distress, impairing quality of life, contributing to stigma, and on acceptance of treatment. In fact, many discontinue treatment because of the sexual side effects.

Effects of Antipsychotics on Prolactin and Sexual Health

The effects of conventional antipsychotics on prolactin are well known. Over 25 years ago, the sustained elevation of serum prolactin to pathological levels by conventional antipsychotics was demonstrated by Meltzer and Fang. The most important factor regulating prolactin is the inhibitory control exerted by dopamine. Any agent that blocks dopamine receptors in a non-selective manner can cause elevation of serum prolactin. Most studies have shown that conventional antipsychotics are associated with a two-to ten-fold increase in prolactin levels.

Prolactin is a hormone in the blood that helps to produce milk and is involved in breast development. However, increased prolactin can lead to a decrease in libido when it is not needed.

The increase in prolactin that occurs through the use of conventional antipsychotics develops over the first week of treatment and remains elevated throughout the period of use. Once treatment stops, prolactin levels return to normal within 2-3 weeks.

In general, second-generation atypical antipsychotics produce lower increases in prolactin than conventional agents. Some agents, including olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon) and clozapine (Clozaril) have been shown to produce no significant or sustained increase in prolactin in adult patients. However, in adolescents (age 9-19 years) treated for childhood-onset schizophrenia or psychotic disorder, it has been shown that after 6 weeks of olanzapine treatment prolactin levels were increased beyond the upper limit of the normal range in 70% of patients.

Second-generation antipsychotics that have been associated with increases in prolactin levels are amisulpride, zotepine and risperidone (Risperidal).

The most common clinical effects of hyperprolactinemia (high prolactin levels) are:

In Women:

• anovulation
• infertility
• amenorrhoea (loss of period)
• decreased libido
• gynaecomastia (swollen breasts)
• galactorrhoea (abnormal breast milk production)

In Men:

• decreased libido
• erectile or ejaculatory dysfunction
• azoospermia (no sperm are present in the ejaculate)
• gynaecomastia (swollen breasts)
• galactorrhoea (occasionally) (abnormal breast milk production)

Less frequently, hirsutism (excessive hairiness) in women, and weight gain have been reported.

Antipsychotics and Sexual Dysfunction Sometimes Tough to Link

Sexual function is a complex area that includes emotions, perception, self-esteem, complex behavior and the ability to initiate and complete sexual activity. Important aspects are the maintenance of sexual interest, the ability to achieve arousal, the ability to achieve orgasm and ejaculation, the ability to maintain a satisfying intimate relationship, and self-esteem. The impact of antipsychotics on sexual functioning is difficult to evaluate, and sexual behavior in schizophrenia is an area in which research is lacking. Data from short-term clinical trials may greatly underestimate the extent of endocrine adverse events.

One thing we do know is that drug-free patients with schizophrenia have lower sexual libido, decreased frequency of sexual thoughts, a decreased frequency of sexual intercourse and higher requirements for masturbation. Sexual activity was also found to be reduced in patients with schizophrenia compared with the general population; 27% of schizophrenia patients reported no voluntary sexual activity and 70% reported having no partner. While untreated schizophrenia patients exhibit decreased sexual desire, neuroleptic treatment is associated with restoration of sexual desire, yet it entails erectile, orgasmic and sexual satisfaction problems.

Atypical antipsychotics are also known to contribute to the development of hyperprolactinaemia. Data for Zyprexa (olanzapine), Seroquel (quetiapine) and Risperdal (risperidone) are published in the Physician's Desk Reference (PDR); a useful reference source since it reports incidence rates for most adverse effects, including EPS, weight gain, and somnolence. The PDR states that "olanzapine elevates prolactin levels, and a modest elevation persists during chronic administration." The following adverse effects are listed as "frequent": decreased libido, amenorrhoea, metrorrhagia (uterine bleeding at irregular intervals), vaginitis. For Seroquel (quetiapine), the PDR states, "an elevation of prolactin levels was not demonstrated in clinical trials", and no adverse effects relating to sexual dysfunction are listed as "frequent". The PDR states that "Risperdal (risperidone) elevates prolactin levels and the elevation persists during chronic administration." The following adverse effects are listed as "frequent": diminished sexual desire, menorrhagia, orgastic dysfunction, and dry vagina.

Management of Hyperprolactinaemia

Before initiating antipsychotic treatment, a careful examination of the patient is necessary. In routine situations, clinicians should examine patients for evidence of sexual adverse events, including menorrhagia, amenorrhoea, galactorrhoea and erectile/ejaculatory dysfunction. If evidence of any such effects are found, then the patient's prolactin level should be measured. This is an important prerequisite to differentiate between adverse effects due to the current medication, those remaining from the previous medication or symptoms of the illness. Furthermore, such checks should be repeated at regular intervals.

The current recommendation is that a rise in prolactin concentrations should not be of concern unless complications develop, and until such time no change in treatment is required. Increased prolactin may be due to the formation of macroprolactin, which does not have serious consequences for the patient. If there are doubts that hyperprolactinemia is related to antipsychotic treatment, other possible causes of the hyperprolactinemia have to be excluded; these include pregnancy, nursing, stress, tumors and other drug therapies.

When treating antipsychotic-induced hyperprolactinemia, decisions should be made on an individual basis after a full and frank discussion with the patient. These discussions should include consideration of the benefits of antipsychotic therapy, as well as the potential impact of any adverse effects. The importance of discussing symptom impact is highlighted by data showing that only a minority of patients discontinue their antipsychotic medication because of breast tenderness, galactorrhoea or menstrual irregularities. However, sexual side-effects are thought to be one of the most important causes of non-compliance. Therefore, the decision whether the current treatment with a prolactin-increasing antipsychotic should be continued or switched to an antipsychotic drug not characteristically associated with increases in prolactin levels has to be made on the basis of the patient's risk-benefit estimation.

Adjunctive therapies have also been tested to reduce the symptoms of hyperprolactinemia, but these are associated with their own risks. Estrogen replacement can prevent the effects of estrogen deficiency but it carries the risk of thromboembolism. Dopamine agonists such as carmoxirole, cabergoline and bromocriptine have been suggested for the management of hyperprolactinemia in patients receiving antipsychotics, but these are associated with side-effects and may worsen psychosis.

Source: Hyperprolactinaemia and Antipsychotic Therapy in Schizophrenia, Martina Hummer and Johannes Huber. Curr Med Res Opin 20(2):189-197, 2004.