Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences

Prolactin Elevation With Antipsychotic Medications:
Mechanisms of Action and Clinical Consequences
Gerald A. Maguire, M.D.
Antipsychotic agents differ in efficacy and side effects such as movement disorders and prolactin eleva- tion because of varying mechanisms of action. A revised nomenclature for antipsychotic agents, which Copyright 2002 Physicians Postgraduate Press, Inc.
categorizes the drugs according to efficacy, risk of movement disorders, and risk of prolactin elevation, isdescribed. Prolactin elevation, a potential side effect of some antipsychotic medications, is underdiagnosedbut can have serious short-term and long-term consequences. Short-term problems include menstrual irregu-larities, sexual dysfunction, and depression. Long-term problems related to prolactin elevation includedecreased bone density and osteoporosis, relapse of psychosis because of poor compliance due to sexualdysfunction or depression, and perhaps cancer, although more research in this area is needed. Despite theserious nature of these effects, prolactin elevation is seldom detected because clinicians often fail to inquireabout sexual function or other symptoms that signal that a patient’s prolactin may be elevated. These areproblems that patients may not bring up with clinicians unless they are asked. Therefore, when patients aretaking antipsychotic medications, clinicians should regularly inquire about sexual dysfunction, depression,menstrual disturbances, galactorrhea, and gynecomastia.
(J Clin Psychiatry 2002;63[suppl 4]:56–62) ecause of varying mechanisms of action, antipsychotic used to describe the 2 major classes of antipsychotics. Agents in agents differ in efficacy and side effects such as move- the newer, atypical antipsychotic class, which were designed to ment disorders and prolactin elevation. Prolactin elevation is a reduce the risk of movement disorders, should be used first-line.
potential side effect of some antipsychotic medications that is These newer antipsychotics were first developed because the underdiagnosed but can have serious short-term and long-term older, typical drugs have a limited efficacy profile, a high risk of consequences. Despite these serious adverse effects, prolactin movement disorders such as extrapyramidal symptoms (EPS) elevation is often not detected because of hesitance on the part and tardive dyskinesia, and a tendency toward prolactin eleva- of the patient to mention the types of problems that elevated pro- tion. All the agents in the atypical class—clozapine, risperidone, lactin causes, such as sexual dysfunction. However, clinicians olanzapine, quetiapine, and ziprasidone—have been introduced can treat patients with agents less likely to lead to elevated pro- more recently than the other drugs and represent an improvement lactin levels. Because the antipsychotic agents’ mechanisms of over the typical agents in some way.
action affect both efficacy and safety profiles, an added advan- Despite being grouped into the same class, the atypical tage of using an antipsychotic that does not raise prolactin is that agents differ in efficacy and safety. Some of the atypical agents efficacy may be improved and the risk of movement disorders are more similar to the typical agents than others. To improve the may be lessened. These 3 factors—efficacy, risk of movement categorization of these agents, a colleague and I1 have proposed disorders, and risk of elevated prolactin—can be used to catego- a revised nomenclature of antipsychotic agents, dividing them into 3 classes rather than 2 (Table 1). In this revised nomencla-ture, we categorized the agents according to their efficacy, risk of movement disorders, and risk of prolactin elevation, which all result from the varying mechanisms of action of the agents.
Nemec and I1 have broken down the antipsychotic agents Antipsychotic agents have been grouped into older and newer into what we call first-generation, second-generation, and third- classes of drugs. The terms typical and atypical are currently generation groups. The category names are not linked to thechronology of when the agents came to market but instead repre-sent advances in antipsychotic technology. For example, cloza- From the Department of Psychiatry/Neuro Psychiatry pine was the first of the so-called atypical agents on the market, Center, University of California, Irvine. but, in our nomenclature, is in the third-generation class because Presented at the roundtable meeting “Safety Profiles of Mood Stabilizers, Antipsychotics, and Broad-Spectrum of its efficacy, low potential for EPS and tardive dyskinesia, and Psychotropics,” which was held August 29–30, 2001, in Amelia lack of prolactin elevation. Clozapine was a revolutionary agent Island, Fla., and supported by an unrestricted educationalgrant from Eli Lilly and Company. in its time but now is approved only for treatment-refractory Reprint requests to: Gerald A. Maguire, M.D., Department schizophrenia due to its potential for agranulocytosis. On the of Psychiatry/Neuro Psychiatry Center, University ofCalifornia, Irvine, 101 South City Drive, Building 3, Orange, other hand, ziprasidone, which is the latest antipsychotic agent to be approved for use in the United States, is in our second- Prolactin Elevation and Antipsychotic Medications Table 1. Revised Nomenclature of Antipsychotic Agentsa
Figure 1. Antipsychotic Agent Mechanisms of Action
Copyright 2002 Physicians Postgraduate Press, Inc.
aData from Maguire and Nemec.1 Abbreviations: EPS = extrapyramidal working memory better than clozapine and olanzapine, but symptoms, TD = tardive dyskinesia, ? = few data available.
these third-generation agents improve verbal fluency better thanrisperidone.9,10 In our nomenclature, the third-generation antipsychotics are generation class. Use of ziprasidone is limited to patients clozapine, olanzapine, and quetiapine. The agents in the third without a vulnerability for cardiovascular disease.2 Under our generation have the lowest risk of movement disorders.11 These system, the third-generation agents, which improved efficacy drugs also spare the patient prolactin elevation, and the spectrum and reduced EPS and tardive dyskinesia while maintaining of efficacy of these agents includes negative symptoms as normal prolactin levels, are the most beneficial.
well as positive symptoms.12 Cognition and mood also are im- In the first-generation class are agents currently known as the proved with these agents over the conventional first-generation conventional or typical antipsychotic agents—haloperidol and drugs10,13 (although further studies are needed for quetiapine, chlorpromazine, for example. These agents cause patients to have a high risk of EPS (which can predict later development oftardive dyskinesia3), they elevate prolactin, and their efficacy in schizophrenia is limited to positive symptoms (delusions and hallucinations).4 They have little effect on negative symptoms ofschizophrenia. In addition, they do not improve—and, in fact, The 3 categories—efficacy, movement disorders, and pro- may impair—mood symptoms and cognition.4 lactin—that distinguish the antipsychotic generations from one Our second-generation class of antipsychotics includes another in our revised nomenclature are effects of dopamine atypical agents such as risperidone and ziprasidone, although blockade in the brain (Figure 1). The dopamine pathways in the ziprasidone is so new that studies are few and results are mixed.
brain that are relevant to efficacy and side effects of antipsychotic Risperidone was the second atypical agent in the U.S. market, agents are the mesolimbic tract, the tuberoinfundibular tract, and following clozapine, and it has efficacy against both positive and the nigrostriatal tract.14 Blockade of dopamine in the tuberoinfun- negative symptoms but a pronounced propensity toward elevat- dibular pathway causes prolactin elevation. Blockade of dopa- ing prolactin levels and a dose-dependent risk of EPS.5 Weiser et mine in the nigrostriatal pathway is the mechanism for extrapy- al.6 found that in 76 patients receiving haloperidol, risperidone, ramidal symptoms and also for tardive dyskinesia, which can be or olanzapine, those with more severe EPS were taking haloperi- attributed to an up-regulation of receptors over time. Dopamine dol or risperidone. Risperidone may improve mood symptoms blockade in the mesolimbic pathway causes the antipsychotic and cognition, although studies are mixed. In terms of mood, effect, and not all atypical antipsychotics are mesolimbic selec- Peuskens et al.7 found in an analysis of double-blind trials of tive. However, the third-generation antipsychotics—olanzapine, risperidone that in patients with anxiety or depressive symptoms clozapine, and quetiapine—are fairly mesolimbic specific in their at baseline, these symptoms decreased significantly more and blockade of dopamine. Because these drugs spare the tubero- also faster with risperidone than with haloperidol. However, infundibular pathway and the nigrostriatal pathway, they have a Ashleigh and Larsen8 reported that in a 10-week trial of risperi- lower risk of movement disorders and a lower risk of prolactin done in patients with schizophrenia, an initial good response to the medication was followed in 46% of the patients by intoler-able affect, including feelings of agitation and depression and periods of crying and insomnia. The authors noted that at base- Seeman and Tallerico15 studied how tightly the antipsychotic line these patients had significantly higher anxiety scores on the agents bind to the dopamine D receptors, and their work pro- Brief Psychiatric Rating Scale. Regarding cognitive function, vides understanding of the efficacy of different agents and their risperidone has shown some improvement in certain areas.
relative risk of causing EPS (Figure 2). Their conclusion was While more effective than haloperidol and the other typical that antipsychotic drugs that elicit movement disorders (such as (or first generation) agents against cognitive dysfunction, ris- haloperidol, chlorpromazine, fluphenazine, ziprasidone, and ris- peridone and the atypical agents differ in areas of cognition peridone) bind more tightly than dopamine to D receptors, that they improve. For example, risperidone seems to improve while those that elicit few or no movement disorders (such as Figure 2. Relative Binding of Antipsychotic Agents to Dopamine D
Table 2. Antipsychotics and Prolactina
Receptorsa
Data from Dickson and Glazer46 and package inserts. Abbreviation: ? = few Copyright 2002 Physicians Postgraduate Press, Inc.
Ziprasidone is indicated for the treatment of schizophrenia, but because of its greater capacity than other antipsychotic agents to prolong the QT interval (which could lead to potentially fatal arrhythmias), other drugs should be tried aAdapted with permission from Seeman and Tallerico.15 thisia by the Barnes Akathisia Scale, and dyskinesia by theAbnormal Involuntary Movement Scale. The lower rates ofEPS with olanzapine than risperidone likely are related to the quetiapine, clozapine, and olanzapine) bind more loosely than fact that olanzapine has more mesolimbic-specific action than dopamine to the D receptors. Seeman and Tallerico concluded that, compared with the tightly bound antipsychotic agents, the Beasley and colleagues18 assessed the incidence of tardive more loosely bound agents generally require fewer days for clini- dyskinesia in patients with schizophrenia who were treated with cal adjustment but require higher clinical doses, and they may olanzapine or haloperidol during the 1-year double-blind phase dissociate from the D receptor more rapidly, which could lead to of their study. For olanzapine, the risk of tardive dyskinesia was relapse earlier than the more tightly bound drugs.
0.52%, while the risk of tardive dyskinesia with haloperidol was Quetiapine is the agent most loosely bound to the dopamine 7.45%. Although these patients were not naive to antipsychotic receptor, which may explain why clinicians often have to admin- treatment, making quantification of the risk of tardive dyskine- ister higher doses of this agent to achieve efficacy. Clozapine is sia to patients newly treated with olanzapine or haloperidol im- about 3 times more tightly bound to the dopamine receptor than possible in this study, these results reflect the incidence of this quetiapine. Olanzapine demonstrates moderate binding and is movement disorder in a clinically relevant population of patients 10-fold more tightly bound to the dopamine D receptor than clo- in their mid-thirties with chronic symptomatology and histories zapine. Even more tightly bound agents are the first- and second- of treatment for more than 10 years.
generation antipsychotic agents. Ziprasidone, chlorpromazine,haloperidol, fluphenazine, and risperidone are tightly bound to the D receptor, which may explain why these agents may have a The normal range of prolactin levels in nonlactating subjects greater risk of EPS. Because the second- and third-generation is between 1 µg/L and 25 µg/L. Kuruvilla et al.19 found that pro- antipsychotic agents have a lower risk of acute EPS than the first- lactin levels in patients with schizophrenia are generally within generation agents do, they may also have a lower risk of tardive the normal range prior to receiving treatment for psychosis; the dyskinesia, because early acute EPS can predict development of schizophrenia itself does not appear to affect prolactin. It is the tardive dyskinesia over the long term. Few clinical data are avail- action of antipsychotic agents that causes the elevation of pro- able on the EPS potential of quetiapine.
lactin. Risperidone and the conventional antipsychotic agents Tollefson et al.16 compared the third-generation antipsychotic raise prolactin levels, but clozapine, quetiapine, and olanzapine agent olanzapine with the first-generation agent haloperidol in are not associated with significant prolactin increase because patients with schizophrenia and related disorders (N = 1996). In they spare dopamine blockade within the tuberoinfundibular the 6-week study, the investigators found a lower risk of treatment- emergent extrapyramidal adverse events among patients taking In a fixed-dose study21 comparing quetiapine with haloperi- olanzapine than in those taking haloperidol. Dystonic, parkinson- dol and placebo in 361 patients with schizophrenia, the prolactin ian, akathisia, and residual events were reported significantly less levels remained essentially flat from baseline to endpoint with often by those taking olanzapine than haloperidol.
quetiapine—even at the highest dosage range—while marked Tran et al.17 conducted a long-term (28-week) study compar- elevations were found with haloperidol.
ing olanzapine with the second-generation antipsychotic ris- There may be a transient increase of prolactin with olanza- peridone. The proportions of patients with treatment-emergent pine in the first few weeks of use, but levels tend to remain spontaneously reported dystonic and parkinsonian events were within the normal range and then return to the baseline levels or significantly smaller with olanzapine than with risperidone.
even lower. In the Tran et al. study17 comparing olanzapine with When EPS were assessed by rating scales, significantly fewer risperidone, a significantly (p < .001) lower proportion of pa- patients taking olanzapine than taking risperidone were found tients in the olanzapine treatment group experienced an eleva- to have pseudoparkinsonism by the Simpson-Angus scale, aka- tion above standard reference ranges in prolactin concentration Prolactin Elevation and Antipsychotic Medications other potential effect of elevated prolactin. These are side effects Table 3. Potential Health Disturbances With Prolactin-Elevating
Antipsychotic Agentsa
that men and women may be hesitant to mention when seeing their physicians, so it is important to inquire about such possible effects. Patients may not expect this type of side effect to occur with medication, and they should be warned in advance if they begin treatment with a prolactin-increasing agent.
Prolactin elevation may also cause sexual dysfunction in both men and women.23 Men may experience prolonged erection or priapism. Men and women may also experience loss of libido Copyright 2002 Physicians Postgraduate Press, Inc.
or fertility and an inability to reach orgasm or ejaculate due to When we talk about improving the quality of life in our pa- tients, we must remember that it is important to consider sexual functioning as a measure of quality of life. Also, maintaining aAbbreviation: ? = few data available.
patients on their medication is key to their achieving reintegra-tion, and their compliance with the medication will be better ifthey do not have sexual dysfunction caused by the medication.
at any time during the study (51.2% vs. 94.4%). In addition, theincreases of prolactin associated with risperidone were more per- sistent than those associated with olanzapine; at endpoint, the Prolactin levels inversely affect estrogen and testosterone proportion of patients taking risperidone whose prolactin levels levels in both men and women. If prolactin is increased, testos- were still elevated was significantly (p < .001) higher than that of terone and estrogen are decreased. This in turn is associated with patients taking olanzapine (90.3% vs. 36%).
decreased bone density, which may predispose patients to osteo- The prolactin increase with risperidone appears to be unre- porosis.20 Patients with schizophrenia are already candidates for lated to dosage. A recent analysis22 of 3 double-blind multicenter osteoporosis because they tend to have other risk factors such as trials in patients taking risperidone dosages of 4 to 12 mg/day, sedentary lifestyle, smoking, poor nutrition, and pathologic haloperidol dosages of 5 to 20 mg/day, or olanzapine dosages water drinking. Therefore, use of an antipsychotic agent that is of 5 to 20 mg/day did not consistently confirm a dose-response unlikely to elevate prolactin levels is important for patients’ relationship for prolactin elevations with any of the drug treat- ments. The authors concluded that risperidone strongly increases Cardiovascular disease is also a risk when estrogen levels are prolactin (by 45–80 µg/L), haloperidol intermediately increases low. Shaarawy et al.26 found that hyperprolactinemia with estro- prolactin (by 17 µg/L), and olanzapine moderately increases pro- gen deficiency produced a significant decrease in nitric oxide lactin (by 1–4 µg/L). Among patients taking risperidone and production, which can predispose patients to certain cardiovas- haloperidol, the mean change in prolactin levels was greater in cular disorders. Elevated blood pressure was associated with the Strungs and colleagues27 reported that animal data have sug- gested that elevated prolactin can lead to breast carcinoma, but studies in humans have been inconclusive. Some human studieshave found increased prolactin levels in patients with breast Some clinicians say they do not see effects of prolactin eleva- cancer and their daughters, but others have not. Strungs et al.
tion and do not understand its importance. They may think that suggested that prolactin may work with stress or estrogen to this side effect does not play a role in their practice. But, in fact, induce breast cancer. Chen and coworkers28 described a human elevated prolactin levels can have many effects on patients, prolactin antagonist that inhibited proliferation of breast cancer whether male or female, in both the short and long term (Table 3).
cells. Prolactin may play a role in endometrial cancer,29 but Clinicians may simply not know about these effects unless they much more research into the relationship between cancer and inquire about them because patients can be reluctant to mention prolactin levels in humans is needed.
them. The effects of hyperprolactinemia usually occur when thepatient’s prolactin level is between 30 µg/L and 60 µg/L or even Comorbid depression can affect all the core symptom do- mains in schizophrenia and can affect all outcome measures. The core symptom domains may be affected in the following ways: Prolactin elevation can cause amenorrhea or an irregular men- positive symptoms may be manifested as mood-congruent strual cycle.20,24 Essentially, typical antipsychotic agents and delusions or hallucinations; negative symptoms may appear as risperidone can induce early menopause.20,23,24 Galactorrhea may apathy and social withdrawal; and cognitive symptoms may in- occur along with menstrual dysfunction.25 Gynecomastia is an- clude impaired concentration and memory. Outcome is affected by depression in the following ways: compliance with treatment agents that spare prolactin tend to have a better effect on depres- may be compromised; social and vocational functioning and re- sion. This may or may not be a cause-and-effect situation but at integration are lessened; and the risk of suicide is increased.
Among patients with schizophrenia, about half will have met There are data on haloperidol in the treatment of stuttering in criteria for major depressive disorder in their lifetime, which is which the drug improved fluency, but 2 to 3 months later much greater than in the general population.30 In the course of patients wanted to stop it because they got depressed.34 They felt schizophrenia, depression can increase the rate of relapse and dysphoric and slowed down. What clinicians have struggled lead to a longer duration of hospitalization, poorer treatment with is how to treat the psychosis without worsening the mood, response, and chronicity of the schizophrenia. Depressive mood and how to treat the mood without worsening the psychosis.
Copyright 2002 Physicians Postgraduate Press, Inc.
in patients with chronic schizophrenia contributes substantially Today, data support use of the third-generation agents for a to overall social dysfunction.31 Management of depression in mood disorder and a comorbid psychotic disorder. The third- patients with schizophrenia is a treatment plan priority.
generation antipsychotics seem to not only avoid the dysphoric Knowing how to treat depression in schizophrenia means side effect of the older agents but also treat the depressive understanding its possible origins. Depression in schizophrenia is brought about by many different causes. One link to post- In the Tollefson et al.35 blinded study of haloperidol versus psychotic depression is difficult to separate from circumstances.
olanzapine in patients with schizophrenia (N = 1996), the total When patients are treated for first-break schizophrenia, they are scores on the Montgomery-Åsberg Depression Rating Scale often depressed 3 or 4 months later. It can be rationalized that (MADRS) were significantly more improved in the olanzapine they are looking ahead at their life and they realize that they are group than in the haloperidol group (p = .001). The authors no longer in school or in the home where they were, so they see stated that mood improvement was indirectly related to im- less potential and see what they have lost.
proved positive, negative, and/or extrapyramidal symptoms, but However, some of this depression—besides reacting to their most of the olanzapine effect on mood was a primary direct new diagnosis—may have been induced by the antipsychotic effect of the medication. In 300 patients with schizoaffective medication. One reason is the extrapyramidal side effects of anti- disorder, Tran et al.36 found that patients taking olanzapine expe- psychotics. Parkinsonian symptoms lead to a greater risk of de- rienced significantly (p ≤ .01) more improvement in depressive pression, and massive dopamine blockade could be dysphoric in symptomatology than those taking haloperidol, as measured by and of itself. Bradykinesia can look like a depression. Akathisia the MADRS total scores. Similarly, when Tran et al.17 compared can lead to anxiety or panic and worsening depression as well.
olanzapine with risperidone in a 6-month trial, olanzapine- But the drugs that have more risk of EPS also tend to cause pro- treated patients improved more on the depression item of the lactin elevation, so there seems to be a relationship between pro- Positive and Negative Syndrome Scale.
lactin and depression. Beyond the menstrual irregularities, sexual In a study37 comparing risperidone with haloperidol, there dysfunction, and potential long-term health concerns that are was a trend for risperidone to improve depressive symptoms possible with hyperprolactinemia, a growing body of evidence slightly more than haloperidol, but the difference was not statis- suggests that prolactin elevation may be associated with depres- tically significant. The mild effect of risperidone in improving sion. Much of this evidence is taken not from the psychiatric depressive symptoms was only statistically significantly greater literature but from the reproductive literature and literature in than that of placebo treatment (p ≤ .05).
endocrinology. For example, in Gynecological Endocrinology, In an open-label study38 of 446 patients taking quetiapine Panay and Studd32 reported that estrogen deficiency, which can compared with 150 taking risperidone, quetiapine showed occur with increased prolactin, mediates mood, cognition, and significantly (p = .028) greater improvement in depressive symptomatology as assessed with the Hamilton Rating Scale for Another theory is that prolactin may have a direct effect on mood, whether it is mediated through estrogen changes or not.
In a study39 comparing ziprasidone with haloperidol in 403 Kellner and colleagues33 reported the results of several studies subjects, significant improvement in depressive symptoms on that they conducted in women with hyperprolactinemia. The the MADRS was found only against placebo, not between the authors found increased depression, anxiety, and hostility, as 2 active drugs (p < .05 for haloperidol 15 mg/day, ziprasidone well as decreased libido, in these women. Prolactin elevation in 40 mg/day, and ziprasidone 200 mg/day; p < .01 for ziprasidone the postpartum stage especially was associated with greater rates of hostility and depression. In these studies, men with hyperpro- Using an agent that improves depression decreases the likeli- lactinemia did not exhibit more hostility than male controls with hood for suicide in patients with schizophrenia. Suicidal behav- normal prolactin levels, and the investigators suggested that ior in schizophrenia is impulsive and unpredictable, and depres- hostility in women with hyperprolactinemia may be an evolu- sion is closely linked to the risk for suicide.40 Close to half of tionary remnant for protecting the young.
patients with schizophrenia attempt suicide, and around 10% Many patients over the years have required both an antipsy- unfortunately complete suicide.41 But olanzapine and clozapine, chotic and an antidepressant; this fact is further indication of as compared with conventional antipsychotics, have been shown a dysphoric side effect of some antipsychotics. However, the to provide a suicide prevention benefit.42 These are the only 2 Prolactin Elevation and Antipsychotic Medications agents that have shown this effect in schizophrenia. When Tran information about special circumstances that might be stressful et al.17 followed 339 patients for 6 months, 1 olanzapine-treated for the patient. If the patient is taking more than one agent, or patient made a suicide attempt, while 7 risperidone-treated if it is unclear whether her menstrual irregularity is caused by stress or medication, it is wise to check the prolactin level.
Ideally, the prolactin level should be tested a couple of times to get a true reading. The measurement should be done in either a nonfasting or a fasting state and at the same time of day bothtimes, so that the results are similar each time.
Prolactin levels can be reduced if they become raised during Once the patient’s prolactin level returns to normal, the asso- Copyright 2002 Physicians Postgraduate Press, Inc.
antipsychotic treatment. Drugs that are not associated with pro- ciated symptoms should resolve. In women, menses will resume, lactin elevation can be used in patients who experience problems libido should increase, and fertility may return to normal for the related to increased prolactin. David et al.22 pointed out that patient’s age and health.24 Estrogen levels should return to age- when patients were switched from haloperidol to olanzapine, appropriate levels, thereby reducing the risks of genitourinary prolactin levels decreased significantly.
symptoms, decreased bone mineral density, and cardiovascular Alternatively, other agents that lower prolactin can be used disease. Psychiatric symptoms and cognitive function may also to augment antipsychotic treatment if the patient should not improve as estrogen levels rise. In men, impotence should be switched from the antipsychotic medication he or she is resolve as prolactin levels decrease.45 Even bone density will taking. Bromocriptine has been an effective treatment for post- improve as the prolactin level improves.
partum depression and hostility.33 Mattox et al.43 found that theprolactin-lowering agents bromocriptine and pergolide each im- proved depression in women with tumors that produce prolactin(prolactinomas) who were studied over 20 weeks. In a case Prolactin elevation is a “Don’t Ask, Don’t Tell” side effect of report44 describing a 28-year-old woman who had taken a certain antipsychotic medications. Patients are unlikely to conventional antipsychotic for 7 years and developed osteoporo- voluntarily report symptoms they find embarrassing. During sis, amenorrhea, and profuse galactorrhea, bromocriptine was antipsychotic treatment check-ups, clinicians need to inquire about galactorrhea and gynecomastia, depressive symptoms, It appears that risperidone raises prolactin levels more than and sexual dysfunction because many patients are reluctant to any other atypical antipsychotic agent on the market does.11,20,24 raise these types of problems without being asked. Prolactin Premenopausal females may have prolactin levels of 100 µg/L elevation is underdiagnosed but can have serious consequences.
or even 200 µg/L when taking risperidone.24 There is less of When selecting antipsychotic treatment for patients, clinicians an absolute effect in males, but the change in prolactin is of must consider the long-term consequences of prolactin elevation concern, as well as the level it reaches.
with its potential effects on short-term and long-term health Prolactin levels should be measured at baseline in patients problems, poor compliance, and depression.
who are beginning treatment with agents that increase prolactinlevels. Then, if clinical symptoms emerge, prolactin levels can Drug names: chlorpromazine (Thorazine and others), clozapine (Clozaril and be remeasured to see if there has been a change. For example, a others), haloperidol (Haldol and others), olanzapine (Zyprexa), pergolide(Permax), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone female patient may have a prolactin level of 35 µg/L, which al- though above the normal range is not that severe. If this patient’sbaseline prolactin level was 10 µg/L, that would mean quite an Disclosure of off-label usage: The author has determined that, to the best of increase had taken place. If her normal level was 25 µg/L, that his knowledge, no investigational information about pharmaceutical agentshas been presented in this article that is outside U.S. Food and Drug would mean only a slight effect on prolactin had occurred. Only the presence of clinical symptoms, not an elevated prolactinlevel alone, should dictate changing a patient’s treatment strat- egy. However, if a patient’s prolactin level is above 100 µg/L, anMRI scan with fine cuts through the sellae should be considered 1. Maguire GA, Nemec C. A revised nomenclature of antipsychotic medica- tions. CNS News: Special Report; Aug. 2–6, 2001 For patients with clinical symptoms of prolactin elevation 2. Geodon (ziprasidone HCl). Physicians’ Desk Reference. Montvale, NJ: who are taking an antipsychotic that is known to raise prolactin 3. Barnes TR, McPhillips MA. Novel antipsychotics, extrapyramidal side levels, switching to a prolactin-sparing agent is the logical treat- effects and tardive dyskinesia. Int Clin Psychopharmacol 1998;13 ment, without necessarily measuring the patient’s prolactin 4. Ichikawa J, Meltzer HY. Relationship between dopaminergic and seroto- level. However, clinicians should remember that symptoms of nergic neuronal activity in the frontal cortex and the action of typical and menstrual irregularity can be brought about by many different atypical antipsychotic drugs. Eur Arch Psychiatry Clin Neurosci 1999; causes and many different medications. If patients are unusually 5. Conley RR. Risperidone side effects. J Clin Psychiatry 2000;61(suppl 8): stressed or in a severe depression, their menstrual cycles can get off course. The patient should be asked questions that will elicit 6. Weiser M, Shneider-Beeri M, Nakash N, et al. Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction 26. Shaarawy M, Nafei S, Abul-Nasr A, et al. Circulating nitric oxide levels in of EPS? Schizophr Res 2000;46(2–3):81–89 galactorrheic, hyperprolactinemic, amenorrheic women. Fertil Steril 1997; 7. Peuskens J, Van Baelen B, De Smedt C, et al. Effects of risperidone on affective symptoms in patients with schizophrenia. Int Clin Psycho- 27. Strungs I, Gray RA, Rigby HB, et al. Two case reports of breast carcinoma associated with prolactinoma. Pathology 1997;29:320–323 8. Ashleigh EA, Larsen PD. A syndrome of increased affect in response to 28. Chen WY, Ramamoorthy P, Chen N, et al. A human prolactin antagonist, risperidone among patients with schizophrenia. Psychiatr Serv 1998;49: hPRL-G129R, inhibits breast cancer cell proliferation through induction of apoptosis. Clin Cancer Res 1999;5:3583–3593 9. Sharma T, Mockler D. The cognitive efficacy of atypical antipsychotics in 29. Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P. Role of exogenous schizophrenia. J Clin Psychopharmacol 1998;18(2, suppl 1):12S–19S and endogenous hormones in endometrial cancer: review of the evidence 10. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanza- and research perspectives. Ann N Y Acad Sci 2001;943:296–315 pine on cognitive function in schizophrenia. Schizophr Bull 1999;25: 30. Bartels SJ, Drake RE. Depression in schizophrenia: current guidelines to Copyright 2002 Physicians Postgraduate Press, Inc.
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