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Norman Sussman, MD

Primary Psychiatry. 2006;13(7):13-14

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What Are the Effects of Antipsychotics on Sexual Functioning?

Henderikus Knegtering, MD, PhD, and Richard Bruggeman, MD, PhD
Needs Assessment: An increasing number of studies reflect a growing awareness of the impact of antipsychotics on sexual functioning. Information from these studies, although still incomplete, has clear consequences in clinical practice. Many clinicians lack an integrated view on the available information and clinical consequences.

Learning Objectives:
• Discuss the pathophysiology of antipsychotic treatment-related sexual side effects. 
• Assess sexual side effects in clinical practice.
• Guide patients with sexual side effects.
• Select the appropriate guidance strategy.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: January 18, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Release date: February 2007. Termination date: February 2009. The estimated time to complete all three articles and the quiz is 3 hours.

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Primary Psychiatry. 2007;14(2):51-56

Dr. Knegtering is head of the Clinical and Research Department for People with Schizophrenia and Related Disorders at the University Medical Center at the University of Groningen in The Netherlands.

Dr. Bruggeman is a psychiatrist in the Clinical and Research Department and a research psychiatrist in the Department of Pharmacology at the University of Groningen. 

Disclosure: Dr. Knegtering is consultant to Eli Lilly and Janssen; and receives research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen. Dr. Bruggeman is on the speaker’s bureaus of Eli Lilly, Janssen, and Organon; and receives research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen.

Please direct all correspondence to: Henderikus Knegtering, MD, PhD, Dept of Psychiatry (UCP), Hanzeplein1, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands; Tel: 31-50-361-2132; Fax: 31-50-361-1699; E-mail: H.Knegtering@psy.umcg.nl.


 

Abstract

This article reviews literature on the relationship between treatment with antipsychotics and change in sexual functioning. Antipsychotics may induce sexual side effects in 30% to 60% of patients. The pharmacologic profile—including receptor-binding profile, passage through the blood-brain barrier, presence of an active metabolite, and elevation of prolactin—may predict the frequency and nature of sexual side effects. There is no evidence that tolerance may develop for sexual side effects after prolonged treatment. Although comparative studies are rare, it is likely that prolactin-sparing antipsychotics induce fewer sexual side effects. The role of other factors, inducing sexual dysfunctions such as sedation, ∝-blockade, testosterone, dopamine, and serotonin, are discussed. Actively addressing possible sexual side effects may prevent underreporting. Switching to a prolactin-sparing antipsychotic, lowering the dosage, or introducing a dopamine agonist or phosphodiesterase inhibitor may assist in clinical guidance.

Introduction

An increasing number of studies reflect a growing awareness of the impact of antipsychotics on sexual functioning. Recent studies also suggest that the occurrence of sexual side effects may be correlated with diminished quality of life and a lower treatment adherence, which often results in a higher relapse rate.1-3 Studies also suggest that the burden of sexual side effects during antipsychotic treatment may equal the burden of some psychotic symptoms.4 This article reviews studies on the occurrence of sexual side effects during treatment with antipsychotics. The study findings are discussed in the context of pharmacologic mechanisms, with focus on clinical implications.

Pharmacologic Properties of Antipsychotics and Sexual Behavior: Dopamine

Pharmacologic properties of antipsychotics predict influences on sexual performance through various mechanisms.5-7 This article focuses on dopaminergic brain systems related to sexual behavior and how antipsychotics may interfere with sexual behavior. Other mechanisms are also discussed.

Approximately 1% of the brain’s neurons use dopamine as a neurotransmitter, and neural nerve endings project in different areas of the brain. Dopaminergic projections to the frontal cortex are typically involved in initiating and terminating behavior and attention, and may include sexual initiative (desire or libido). Projections to limbic brain areas are typically involved in emotion and reward systems, including sexual reward (orgasm). Dopamine in the tuberoinfundibular system is the main factor in regulating prolactin secretion in the blood through the anterior pituitary gland. Elevation of prolactin, which has many physiologic functions, is associated with sexual dysfunction, although its mechanism is being debated. Overall, the dopamine system is directly and, through prolactin, indirectly involved in sexual functioning. This includes most phases of sexual behavior such as libido and orgasm (quantitative and qualitative), and possibly arousal (erection and vaginal lubrication).

All antipsychotics are postsynaptic dopamine antagonists. Researchers have found that blocking endogenous dopamine in the limbic system (approximately 70% postsynaptic receptor blocking) is considered necessary for antipsychotic activity. A higher dosage, brain penetration, and affinity to the dopamine receptor predict increased competition with endogenous dopamine. The extent of postsynaptic dopamine blocking varies between antipsychotics and affinity to the post-synaptic dopamine receptor as well as dosage and other pharmacologic properties, such as brain penetration.

Postsynaptic dopamine blocking by antipsychotics in the tuberoinfundibular system of the brain interferes with the physiologic inhibition of prolactin release, which leads to prolactin elevation. Research has suggested that a secondary effect of prolactin increase may be a blood-level decrease of estrogen and testosterone that may also contribute to an inhibition in sexual behavior.

Interestingly, some newly developed antipsychotics, such as aripiprazole, exert mixed dopamine antagonistic and agonistic properties. Thus, the final effects of aripiprazole on sexual performance are difficult to predict from its pharmacologic profile.

Other Antipsychotic Pharmacologic PropertieS that Interfere with Sexual Functioning

Many antipsychotics have sedating properties, partly due to their action as histamine antagonists, that may interfere with sexual performance, especially by diminishing sexual desire. Some antipsychotics block noradrenergic systems, including a1-receptors. These noradrenergic effects, which may balance cholinergic effects, lead to final effects on erection. On rare occassions, these effects may contribute to priapism, but more often they contribute to erection disturbance. Blocking a1-receptors may also interfere with ejaculation. Although mechanisms are under debate (including retrograde ejaculation), patients treated with a1-blocking agents often report a reduced volume or the absence of ejaculate despite the experience of orgasm remaining the same (dry ejaculation).

Modern antipsychotics typically show anti-serotonergic properties, including blocking serotonin (5-HT)2A or 5-HT2C receptors. Serotonergic mechanisms are associated with sexual side effects. While little has been investigated, this may be partly corrected through 5-HT2A-blocking properties of some antipsychotics. The main mechanisms and effects of antipsychotics on sexual performance are summarized in Table 1.

Frequency, Impact, and Course of Sexual Dysfunctions During Treatment with Antipsychotics

Clinical Trials on Sexual Performance

Clinical trials that assess sexual side effects of antipsychotics, especially comparative studies, are rare.8-10 Studies using spontaneous reports from patients suggest low incidences of sexual dysfunctions.10,11 In contrast, studies using structured interviews or questionnaires tend to report high incidences (30% to 60% and higher) of sexual side effects related to treatment with antipsychotics.7,12,13 The differences in sexual dysfunction prevalence depend on the method used to evaluate these effects—such as spontaneous report, a self-report questionnaire, or an interview or semi-structured interview—training of interviewers as well as the cultural background of patients and interviewers. Other factors that may influence dysfunction reports are related to the study design, age and diagnosis of the participants, type of antipsychotic, and dosage. This variation between study designs limits comparison between studies. Understanding these limitations, this article reviews the main findings from studies evaluating undesired effects of antipsychotics on sexual performance. Only studies using formal questionnaires evaluating dimensions like libido, arousal, orgasm, and ejaculation are included.

First-Generation (Classical) Antipsychotics

Patients treated with first-generation classical antipsychotics report 30% to 50% sexual dysfunction.14-16 Classical antipsychotics are reported to affect sexual desire, erectile functioning, orgasm, and sexual satisfaction in about the same frequency. Although there are few comparative studies, the majority of literature suggests that antipsychotics may differ in the type and frequency of reported sexual dysfunctions.16,17 For example, thioridazine appears to cause more sexual dysfunctions (erection and ejaculation dysfunction) in comparison to other classical antipsychotics.18 These finding are consistent with anticholinergic and the α1-blocking properties of thioridazine. Smith and colleagues16 also suggest that there may be differences between classical antipsychotics in the frequency and pattern of sexual side effects, but more detailed studies are lacking.

Second-Generation (Atypical) Antipsychotics

Clozapine was the first second-generation (atypical) antipsychotic introduced. Clozapine, which has a low affinity to the dopamine receptor, induces no sustained prolactin elevation. Sedative properties predict an influence on sexual desire, while α1-blocking properties may predict an influence on ejaculation. Accordingly, most authors report relatively low frequencies of erectile and orgasm dysfunctions in comparison to most classical antipsychotics. Reduction in ejaculatory volume and sexual desire are reported, which are in line with the sedative and α1-blocking properties of clozapine.7,15,19-22

Quetiapine shares many pharmacologic properties with clozapine, including sedation, a low affinity for the dopamine receptor, no sustained prolactin elevation, and α1-blocking properties. The majority of studies comparing quetiapine with risperidone or other classical antipsychotics suggest that quetiapine may induce fewer sexual side effects, with the most commonly reported effects being reduction in sexual desire and ejaculation disturbance.11,22,23

Olanzapine has modest sedative properties and, in comparison to most classical antipsychotics, an intermediate affinity to dopamine receptors, which is consistent with a low, dose-dependent tendency to elevate prolactin. In studies with a dosage of olanzapine 15 mg/day, olanzapine appears to induce fewer sexual side effects in comparison to classical antipsychotics and risperidone (3–5 mg/day).7,22,24 Literature suggests that at higher dosages (>15 mg/day), the frequency of sexual side effects (as well as prolactin levels) during treatment with olanzapine may increase and equal frequencies during treatment with risperidone.23

Risperidone has low sedating effects and a high affinity for the dopamine receptor. Risperidone and its active metabolite 9-OH risperidone elevate prolactin levels much more than most other second-generation antipsychotics and classical antipsychotics. In most comparative studies, risperidone (3–5 mg/day) appears to more frequently induce sexual side effects in comparison to comparable dosages of most classical antipsychotics, olanzapine (<15 mg/day), quetiapine, or clozapine.7,11,24 Risperidone appears to have inhibiting effects on all dimensions of sexual functioning, including desire, erection, vaginal lubrication, orgasm, and ejaculation.

Amisulpride is a selective dopamine antagonist; it combines a relative low brain penetration with a low affinity for the dopamine (D)2 and D3 receptors. In therapeutic dosages, this results in a pronounced prolactin elevation that is higher than classical antipsychotics and risperidone. The influence of amisulpride on sexual performance has been little investigated. One study suggested that amisulpride may induce sexual side effects in a high frequency, comparable to risperidone and classical antipsychotics, which is in line with high serum prolactin elevation.22

Aripiprazole has a strong affinity for the dopamine receptor. Its mixed agonist/antagonist effects for the dopamine receptor result in a slight reducing effect on prolactin levels. One study showed that switching from previous antipsychotics to aripiprazole may lead to a significant reduction in serum prolactin levels and some improvement of sexual functioning.25 At the University Medical Center Groningen in The Netherlands, several studies on sexual side effects of antipsychotics have been performed using the same instruments, always after 6 weeks of treatment.26 Table 2 summarizes the main findings from these studies.26 Methodologic limitations, like data from naturalistic and open single-blind randomized studies, should be considered.

Evaluating Sexual Dysfunctions

In general, without a structured interview, side effects are under-reported and sexual side effects are reported in a lower frequency. Evaluating undesired treatment effects in the context of evaluating the desired treatment effects is an important task of every clinician. Reasons for side effect under-reporting are time restraints, patients and clinicians not being able to distinguish between treatment-related and illness-related symptoms, clinicians being uninformed about possible side effects, difficulties in memorizing side effects during clinical evaluation, and, particularly for sexual side effects, taboo aspects for clinicians and patients. Explicitly addressing side effects using a questionnaire is the best way to evaluate undesired treatment effects.10,24 It is important to discuss sexual side effects in a clear time frame (eg, “last 2 weeks” or “last month”). In studies on sexual side effects at the University Medical Center at the University of Groningen, researchers inquired on patients’ sexual functioning during the previous 2 weeks of treatment with antipsychotics. During a questionnaire, researchers stated:

Some patients notice changes in their sexual desires and functioning after using antipsychotics. Sometimes changes are noted during sexual intercourse with a partner or during sexual self-stimulation. Some patients relate an improvement in sexual functioning, others a worsening. Did you notice a change in your sexual desire or interest in the past 4–6 weeks, for example more or less interest in sex?26

A recent study showed that two screenings questions may predict the outcome of a full-screening instrument called the Arizona Sexual Experience Scale.27 Screening questions were, “Can I ask if you have recently had any side effects from your medicines?” and “Have your medicines caused problems with your sexual functioning recently?” If patients respond “No” to both screening questions, there is little chance of finding sexual dysfunctions after further exploration. When patients respond “Yes” to the screening questions, sexual dysfunction and the possible burden should be explored in order to judge the necessity for further clinical guidance or intervention.

When sexual side effects are present, it is important to know which are present and what the burden may be for the patient in the context of desired clinical effects. Treatment history and available treatment alternatives should be included in discussion with the patient about possible consequences.

Possible Solutions for Sexual Side Effects of Antipsychotics

Education of the Patient

Some patients experience sexual side effects but do not consider the effects to be a problem. In such cases, clinicians may find that explaining the nature of the side effects is sufficient. Particularly when men experience a diminished volume of ejaculation—sometimes becoming the cause of worry—the problem may be well addressed by explaining that it is a reversible treatment-related effect. Studies comparing sexual side effects after a short treatment period, such as 6 weeks, show the same frequencies of sexual side effects in comparison to long-term treatment periods over many years.12,21 Since tolerance for sexual side effects appears not to develop, it would not be helpful to wait for the spontaneous recovery of sexual side effects. Although tolerance is not to be expected, sexual side effects typically appear to be reversible. One exception is priapism, which should be considered an emergency; referring to a specialized center for immediate treatment may prevent irreversible erectile dysfunction.

When sexual side effects are reported, patients should be informed about the nature of these effects and treatment options. Some patients will tend to accept these side effects; others will want to explore alternative treatment options.

Dose Reduction

Some studies suggest that sexual side effects may be related to dosage.26 For this reason, as long as treatment remains effective, lowering the dosage could be considered for patients experiencing sexual side effects.

Switching Strategies in General

Often dosage lowering is not possible as the treatment may decrease in efficacy. Depending on what dimension of sexual performance may be involved, switching to a less sedative antipsychotic (reduction of sexual desire) or switching to an antipsychotic with less α1-blocking properties (dry ejaculation) could be considered.5,7,13

Switching Strategies from a Prolactin-Elevating to a Prolactin-Sparing Antipsychotic

Antipsychotics may influence many dimensions of sexual functioning, and switching to a less prolactin-elevating antipsychotic may be considered. Prolactin elevation may be an expression of dopamine blocking in the pituitary gland. In most antipsychotics, this is closely correlated to dopamine blocking in other brain areas. Switching from a prolactin-elevating antipsychotic to a prolactin-sparing antipsychotic may diminish several dimensions of sexual side effects. This switch strategy was investigated in four studies.26,28-30 In a randomized, double-blind study, switched patients with sexual dysfunction were treated with classical antipsychotics (n=27) or risperidone (n=12, 4 mg/day) versus fluphenazine (n=9, 12.5 mg/day) or quetiapine (n=6, 400 mg/day).28 Patients switching to quetiapine reported a significant improvement in sexual performance (improvement of arousal and a trend in improvement of libido).

In a study of 20 female patients with sexual side effects treated with risperidone (mean dosage=3.5 mg/day), the patients were switched to olanzapine (mean dosage=9.1 mg/day).29 The switch resulted in a reduction of reported sexual side effects, from 50% to 30%. In an open, randomized study, 50% of patients treated with risperidone (n=29) or classical antipsychotics (n=25) were switched to olanzapine (mean dosage=12.8 mg/day).30 Patients switched to olanzapine (n=27) reported a significant reduction in sexual side effects. The findings are similar to a naturalistic follow-up study evaluating sexual dysfunction in 18 patients with sexual side effects treated with a prolactin-elevating antipsychotic.26 After the patients were switched to a prolactin-sparing antipsychotic, 14 out of 18 patients found that their sexual side effects had disappeared.

Treatment with a Dopamine Agonist

As dopamine blocking appears to be important for antipsychotic action, treatment with a dopamine agonist for sexual side effects seems counterintuitive. In theory, dopamine agonists may be effective in the treatment of sexual side effects, but they may also increase psychotic symptoms. Dopamine agonists that have been studied and shown to be effective are bromocriptine (5.0–7.5 mg/day) and cabergoline (.125–.250 mg/week to 2 mg/week).31-33 These studies suggest that dopamine agonists may be safe, but, as expected, some patients experienced an increase in psychotic symptoms. Although not studied in patients treated with antipsychotics, apomorfine (a short-acting dopamine agonist) could also be a useful treatment alternative. It is important to note that treatment with dopamine agonists implies experimental off-label use of these medications.

Treatment with a Phosphodiesterase Inhibitor

Several phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil) are marketed for treatment of erectile dysfunction. Case reports suggest that phosphodiesterase inhibitors may improve erectile dysfunction in treatment with antipsychotics. Recently, a double-blind, crossover, placebo-controlled study showed that sildenafil was effective and well-tolerated in the treatment of antipsychotic-induced erectile dysfunction.34

Conclusion

Sexual dysfunctions related to treatment with antipsychotics are studied infrequently. Most are open studies using miscellaneous designs and questionnaires.

Although <10% of patients spontaneously mention sexual dysfunctions, in response to structured questionnaires 40% to 60% of patients reported experiencing sexual dysfunctions that they attributed to the use of classical antipsychotics or risperidone. Although studies have found differing results, reduction of desire and orgasm disturbances are found in men and women in approximately the same frequency. In addition, comparative studies are rare; it appears that prolactin-sparing antipsychotics induce sexual dysfunction less frequently. In randomized studies of olanzapine and quetiapine versus risperidone, prolactin-sparing effects of olanzapine and quetiapine are associated with significantly less sexual dysfunction.

Serum prolactin elevation and dopamine blocking may be important factors in inducing sexual dysfunctions. Additional studies and studies with standardized assessment methods that compare antipsychotics and their tendency to induce sexual side effects are needed. Studies on the pathogenetic mechanisms and the long-term effects on social behavior and health risks are needed as well.

Although particular studies show that sexual side effects are important to patients and may influence compliance, other studies show that both patients and clinicians are reluctant to discuss such effects.4,10,35 Clinicians should actively query for antipsychotic side effects, in particular sexual side effects, to give optimal guidance. A majority of patients appreciate when clinicians systematically ask for side effects, including sexual side effects. Dose reduction or switching to a prolactin-sparing antipsychotic is effective in reducing sexual side effects. In some cases, adding bromocriptine, amantadine, apomorfine, or another dopamine agonist may be an alternative. For patients predominantly experiencing erectile dysfunction, phosphodiesterase inhibitors may be a treatment option. PP

References

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2. Kelly DL, Conley RR. Sexuality and schizophrenia: a review. Schizophr Bull. 2004;30(4):767-779.

3. Olfson M, Uttaro T, Carson WH, Tafesse E. Male sexual dysfunction and quality of life in schizophrenia. J Clin Psychiatry. 2005;66(3):331-338.

4. Finn SE, Baily JM, Schultz RT, Faber R. Subjective utility ratings of neuroleptics in treating schizophrenia. Psychol Med. 1990;20(4):843-848.

5. Meston CM, Frohlich PF. The neurobiology of sexual function. Arch Gen Psychiatry. 2000;57(11):1012-1030.

6. Segraves RT. Effects of psychotropic drugs on human erection and ejaculation. Arch Gen Psychiatry. 1989;46(3):275-284.

7. Knegtering H, van der Moolen AE, Castelein S, Kluiter H, van der Bosch RJ. What are the effects of antipsychotics on sexual dysfunctions and endocrine function? Psychoneuroendocrinology. 2003;28(suppl 2):109-123.

8. Nestoros JN, Lehmann HE, Ban TA. Sexual behavior of the male schizophrenic: the impact of illness and medications. Arch Sex Behav. 1981;10(5):421-442.

9. Knegtering H, Lambers PA, Prakken G, Ten Brink C. Serum prolactin levels and sexual dysfunction in antipsychotic medication, such as risperidone: a review. Acta Neuropsychiatr. 2000;12(1):19-26.

10. Peuskens J, Sienaert P, DeHert M. Sexual dysfunction: the unspoken side of antipsychotics. Eur Psychiatry. 1998;13(suppl):23-30.

11. Knegtering H, Castelein S, Bous H, et al. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. J Clin Psychopharmacol. 2004;24(1):56-61.

12. Lingjearde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100.

13. Sullivan G, Lukoff D. Sexual side effects of antipsychotic medication: evaluation and interventions. Hosp Community Psychiatry. 1990;41(11):1238-1241.

14. Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis. 1982;170(8):463-467.

15. Hummer M, Kemmler G, Kurz M, Kurzhaler I, Oberbauer H, Fleischhacker WW. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry. 1999;156(4):631-633.

16. Smith S, Wheeler M, O’Keane V, Murray R. Antipsychotics and hypogonadism in patients with schizophrenia. Schizophr Res. 2000;41(1):218.

17. Knegtering H, Blijd C, Boks M. Sexual dysfunctions and prolactin levels in patients using classical antipsychotics, risperidone or olanzapine. Schizophr Res. 1999;36(1-3):355.

18. Kotin J, Wilbert DE, Verburg D, Soldinger SM. Thioridazine and sexual dysfunction. Am J Psychiatry. 1976;133(1):82-85.

19. Crenshaw TL, Goldberg JP. Sexual Pharmacology: Drugs That Affect Sexual Functioning. London, England: W.W. Norton & Company; 1996.

20. Aizenberg D, Modai I, Landa A, Gil-Ad I, Weizman A. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry. 2001;62(7):541-544.

21. Castelein S, Knegtering H, Beintema H, et al. The long-term effects of depot antipsychotics or clozapine on sexual functioning. Schizophr Res. 2004;67(1 suppl):181.

22. Lambert M, Haro JM, Novick D, et al. Olanzapine vs. other antipsychotics in actual out-patient settings: six months tolerability results from the European Schizophrenia Out-patient Health Outcomes study. Acta Psychiatr Scand. 2004;111(3):232-243.

23. Byerly MJ, Nakonezny PA, Bettcher BM, Carmody T, Fisher R, Rush AJ. Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine. Schizophr Res. 2006;86(1-3):244-250.

24. Knegtering H, Boks M, Blijd C, Castelein C, van den Bosch RJ, Wiersma D. A randomized open-label comparison of the impact of olanzapine versus risperidone on sexual functioning. J Sex Marital Ther. 2006;32(4):315-326.

25. Hanssen L, L’Italien G, Marcus R, McQuade R, Carson W, Beuzen JN. Sexual dysfunction in a naturalstic, open-labl study of arirpiprazole and standard of care of community-treated patients with schizophrenia (The STAR Trial). Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada.

26. Knegtering H. Antipschotic treatment and sexual functioning, role of prolactin. Available at: http://irs.ub.rug.nl/ppn/254939104. Accessed January 8, 2007.

27. Byerly MJ, Nakonezny PA, Fisher R, Magouirk B, Rush AJ. An empirical evaluation of the Arizona Sexual Experience scale and a simple one-item screening test for assessing antipsychotic-related sexual dysfunction in outpatients with schizophrenia and schizoaffective disorder. Schizophr Res. 2006;81(2-3):311-316.

28. Kelly DL, Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology. 2006;31(3):340-346.

29. Kim KS, Pae CU, Chea JH, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiary. 2002;63(5):408-413.

30. Kinon BJ, Ahl J, Liu-Seifert H, Maguire GA. Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine. Psychoneuroendocrinology. 2006;31(5):577-588.

31. Matsuoka I, Nakai T, Miyake M, Hirai M, Ikawa G. Effects of bromocriptine on neuroleptic-induced amenorrhea, galactorrhea and impotence. Jpn J Psychiatry Neurol. 1986;40(4):639-646.

32. Cohen LG, Biederman J. Treatment of risperidone-induced hyperprolactinemia with a dopamine agonist in children. J Child Adolesc Psychopharmacol. 2001;11(4):435-440.

33. Cavallaro R, Cocchi F, Angelone SM, Lattuada E, Smeraldi E. Cabergoline treatment of risperidone-induced hyperprolactinemia: a pilot study. J Clin Psychiatry. 2004;65(2):187-190.

34. Gopalakrishan R, Jacob KS, Kuruvilla A, Vasantharaj B, John JK. Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry. 2006;163(3):494-499.

35. Strauss B, Gross J. Psychopharmak bedingte Veranderungen der Sexualitat (Haufigkeit und Stellwert in der psychiatrischen Praxis). Psychiatr Prax. 1984;11(2):49-55.

 

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Journal CMEs

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Henderikus Knegtering, MD, PhD, and Richard Bruggeman, MD, PhD
Needs Assessment: An increasing number of studies reflect a growing awareness of the impact of antipsychotics on sexual functioning. Information from these studies, although still incomplete, has clear consequences in clinical practice. Many clinicians lack an integrated view on the available information and clinical consequences.

Learning Objectives:
• Discuss the pathophysiology of antipsychotic treatment-related sexual side effects. 
• Assess sexual side effects in clinical practice.
• Guide patients with sexual side effects.
• Select the appropriate guidance strategy.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: January 18, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Release date: February 2007. Termination date: February 2009. The estimated time to complete all three articles and the quiz is 3 hours.

Primary Psychiatry. 2007;14(2):51-56

Dr. Knegtering is head of the Clinical and Research Department for People with Schizophrenia and Related Disorders at the University Medical Center at the University of Groningen in The Netherlands.

Dr. Bruggeman is a psychiatrist in the Clinical and Research Department and a research psychiatrist in the Department of Pharmacology at the University of Groningen. 

Disclosure: Dr. Knegtering is consultant to Eli Lilly and Janssen; and receives research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen. Dr. Bruggeman is on the speaker’s bureaus of Eli Lilly, Janssen, and Organon; and receives research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen.

Please direct all correspondence to: Henderikus Knegtering, MD, PhD, Dept of Psychiatry (UCP), Hanzeplein1, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands; Tel: 31-50-361-2132; Fax: 31-50-361-1699; E-mail: H.Knegtering@psy.umcg.nl.


 

Abstract

This article reviews literature on the relationship between treatment with antipsychotics and change in sexual functioning. Antipsychotics may induce sexual side effects in 30% to 60% of patients. The pharmacologic profile—including receptor-binding profile, passage through the blood-brain barrier, presence of an active metabolite, and elevation of prolactin—may predict the frequency and nature of sexual side effects. There is no evidence that tolerance may develop for sexual side effects after prolonged treatment. Although comparative studies are rare, it is likely that prolactin-sparing antipsychotics induce fewer sexual side effects. The role of other factors, inducing sexual dysfunctions such as sedation, ∝-blockade, testosterone, dopamine, and serotonin, are discussed. Actively addressing possible sexual side effects may prevent underreporting. Switching to a prolactin-sparing antipsychotic, lowering the dosage, or introducing a dopamine agonist or phosphodiesterase inhibitor may assist in clinical guidance.

Introduction

An increasing number of studies reflect a growing awareness of the impact of antipsychotics on sexual functioning. Recent studies also suggest that the occurrence of sexual side effects may be correlated with diminished quality of life and a lower treatment adherence, which often results in a higher relapse rate.1-3 Studies also suggest that the burden of sexual side effects during antipsychotic treatment may equal the burden of some psychotic symptoms.4 This article reviews studies on the occurrence of sexual side effects during treatment with antipsychotics. The study findings are discussed in the context of pharmacologic mechanisms, with focus on clinical implications.

Pharmacologic Properties of Antipsychotics and Sexual Behavior: Dopamine

Pharmacologic properties of antipsychotics predict influences on sexual performance through various mechanisms.5-7 This article focuses on dopaminergic brain systems related to sexual behavior and how antipsychotics may interfere with sexual behavior. Other mechanisms are also discussed.

Approximately 1% of the brain’s neurons use dopamine as a neurotransmitter, and neural nerve endings project in different areas of the brain. Dopaminergic projections to the frontal cortex are typically involved in initiating and terminating behavior and attention, and may include sexual initiative (desire or libido). Projections to limbic brain areas are typically involved in emotion and reward systems, including sexual reward (orgasm). Dopamine in the tuberoinfundibular system is the main factor in regulating prolactin secretion in the blood through the anterior pituitary gland. Elevation of prolactin, which has many physiologic functions, is associated with sexual dysfunction, although its mechanism is being debated. Overall, the dopamine system is directly and, through prolactin, indirectly involved in sexual functioning. This includes most phases of sexual behavior such as libido and orgasm (quantitative and qualitative), and possibly arousal (erection and vaginal lubrication).

All antipsychotics are postsynaptic dopamine antagonists. Researchers have found that blocking endogenous dopamine in the limbic system (approximately 70% postsynaptic receptor blocking) is considered necessary for antipsychotic activity. A higher dosage, brain penetration, and affinity to the dopamine receptor predict increased competition with endogenous dopamine. The extent of postsynaptic dopamine blocking varies between antipsychotics and affinity to the post-synaptic dopamine receptor as well as dosage and other pharmacologic properties, such as brain penetration.

Postsynaptic dopamine blocking by antipsychotics in the tuberoinfundibular system of the brain interferes with the physiologic inhibition of prolactin release, which leads to prolactin elevation. Research has suggested that a secondary effect of prolactin increase may be a blood-level decrease of estrogen and testosterone that may also contribute to an inhibition in sexual behavior.

Interestingly, some newly developed antipsychotics, such as aripiprazole, exert mixed dopamine antagonistic and agonistic properties. Thus, the final effects of aripiprazole on sexual performance are difficult to predict from its pharmacologic profile.

Other Antipsychotic Pharmacologic PropertieS that Interfere with Sexual Functioning

Many antipsychotics have sedating properties, partly due to their action as histamine antagonists, that may interfere with sexual performance, especially by diminishing sexual desire. Some antipsychotics block noradrenergic systems, including a1-receptors. These noradrenergic effects, which may balance cholinergic effects, lead to final effects on erection. On rare occassions, these effects may contribute to priapism, but more often they contribute to erection disturbance. Blocking a1-receptors may also interfere with ejaculation. Although mechanisms are under debate (including retrograde ejaculation), patients treated with a1-blocking agents often report a reduced volume or the absence of ejaculate despite the experience of orgasm remaining the same (dry ejaculation).

Modern antipsychotics typically show anti-serotonergic properties, including blocking serotonin (5-HT)2A or 5-HT2C receptors. Serotonergic mechanisms are associated with sexual side effects. While little has been investigated, this may be partly corrected through 5-HT2A-blocking properties of some antipsychotics. The main mechanisms and effects of antipsychotics on sexual performance are summarized in Table 1.

Frequency, Impact, and Course of Sexual Dysfunctions During Treatment with Antipsychotics

Clinical Trials on Sexual Performance

Clinical trials that assess sexual side effects of antipsychotics, especially comparative studies, are rare.8-10 Studies using spontaneous reports from patients suggest low incidences of sexual dysfunctions.10,11 In contrast, studies using structured interviews or questionnaires tend to report high incidences (30% to 60% and higher) of sexual side effects related to treatment with antipsychotics.7,12,13 The differences in sexual dysfunction prevalence depend on the method used to evaluate these effects—such as spontaneous report, a self-report questionnaire, or an interview or semi-structured interview—training of interviewers as well as the cultural background of patients and interviewers. Other factors that may influence dysfunction reports are related to the study design, age and diagnosis of the participants, type of antipsychotic, and dosage. This variation between study designs limits comparison between studies. Understanding these limitations, this article reviews the main findings from studies evaluating undesired effects of antipsychotics on sexual performance. Only studies using formal questionnaires evaluating dimensions like libido, arousal, orgasm, and ejaculation are included.

First-Generation (Classical) Antipsychotics

Patients treated with first-generation classical antipsychotics report 30% to 50% sexual dysfunction.14-16 Classical antipsychotics are reported to affect sexual desire, erectile functioning, orgasm, and sexual satisfaction in about the same frequency. Although there are few comparative studies, the majority of literature suggests that antipsychotics may differ in the type and frequency of reported sexual dysfunctions.16,17 For example, thioridazine appears to cause more sexual dysfunctions (erection and ejaculation dysfunction) in comparison to other classical antipsychotics.18 These finding are consistent with anticholinergic and the α1-blocking properties of thioridazine. Smith and colleagues16 also suggest that there may be differences between classical antipsychotics in the frequency and pattern of sexual side effects, but more detailed studies are lacking.

Second-Generation (Atypical) Antipsychotics

Clozapine was the first second-generation (atypical) antipsychotic introduced. Clozapine, which has a low affinity to the dopamine receptor, induces no sustained prolactin elevation. Sedative properties predict an influence on sexual desire, while α1-blocking properties may predict an influence on ejaculation. Accordingly, most authors report relatively low frequencies of erectile and orgasm dysfunctions in comparison to most classical antipsychotics. Reduction in ejaculatory volume and sexual desire are reported, which are in line with the sedative and α1-blocking properties of clozapine.7,15,19-22

Quetiapine shares many pharmacologic properties with clozapine, including sedation, a low affinity for the dopamine receptor, no sustained prolactin elevation, and α1-blocking properties. The majority of studies comparing quetiapine with risperidone or other classical antipsychotics suggest that quetiapine may induce fewer sexual side effects, with the most commonly reported effects being reduction in sexual desire and ejaculation disturbance.11,22,23

Olanzapine has modest sedative properties and, in comparison to most classical antipsychotics, an intermediate affinity to dopamine receptors, which is consistent with a low, dose-dependent tendency to elevate prolactin. In studies with a dosage of olanzapine 15 mg/day, olanzapine appears to induce fewer sexual side effects in comparison to classical antipsychotics and risperidone (3–5 mg/day).7,22,24 Literature suggests that at higher dosages (>15 mg/day), the frequency of sexual side effects (as well as prolactin levels) during treatment with olanzapine may increase and equal frequencies during treatment with risperidone.23

Risperidone has low sedating effects and a high affinity for the dopamine receptor. Risperidone and its active metabolite 9-OH risperidone elevate prolactin levels much more than most other second-generation antipsychotics and classical antipsychotics. In most comparative studies, risperidone (3–5 mg/day) appears to more frequently induce sexual side effects in comparison to comparable dosages of most classical antipsychotics, olanzapine (<15 mg/day), quetiapine, or clozapine.7,11,24 Risperidone appears to have inhibiting effects on all dimensions of sexual functioning, including desire, erection, vaginal lubrication, orgasm, and ejaculation.

Amisulpride is a selective dopamine antagonist; it combines a relative low brain penetration with a low affinity for the dopamine (D)2 and D3 receptors. In therapeutic dosages, this results in a pronounced prolactin elevation that is higher than classical antipsychotics and risperidone. The influence of amisulpride on sexual performance has been little investigated. One study suggested that amisulpride may induce sexual side effects in a high frequency, comparable to risperidone and classical antipsychotics, which is in line with high serum prolactin elevation.22

Aripiprazole has a strong affinity for the dopamine receptor. Its mixed agonist/antagonist effects for the dopamine receptor result in a slight reducing effect on prolactin levels. One study showed that switching from previous antipsychotics to aripiprazole may lead to a significant reduction in serum prolactin levels and some improvement of sexual functioning.25 At the University Medical Center Groningen in The Netherlands, several studies on sexual side effects of antipsychotics have been performed using the same instruments, always after 6 weeks of treatment.26 Table 2 summarizes the main findings from these studies.26 Methodologic limitations, like data from naturalistic and open single-blind randomized studies, should be considered.

Evaluating Sexual Dysfunctions

In general, without a structured interview, side effects are under-reported and sexual side effects are reported in a lower frequency. Evaluating undesired treatment effects in the context of evaluating the desired treatment effects is an important task of every clinician. Reasons for side effect under-reporting are time restraints, patients and clinicians not being able to distinguish between treatment-related and illness-related symptoms, clinicians being uninformed about possible side effects, difficulties in memorizing side effects during clinical evaluation, and, particularly for sexual side effects, taboo aspects for clinicians and patients. Explicitly addressing side effects using a questionnaire is the best way to evaluate undesired treatment effects.10,24 It is important to discuss sexual side effects in a clear time frame (eg, “last 2 weeks” or “last month”). In studies on sexual side effects at the University Medical Center at the University of Groningen, researchers inquired on patients’ sexual functioning during the previous 2 weeks of treatment with antipsychotics. During a questionnaire, researchers stated:

Some patients notice changes in their sexual desires and functioning after using antipsychotics. Sometimes changes are noted during sexual intercourse with a partner or during sexual self-stimulation. Some patients relate an improvement in sexual functioning, others a worsening. Did you notice a change in your sexual desire or interest in the past 4–6 weeks, for example more or less interest in sex?26

A recent study showed that two screenings questions may predict the outcome of a full-screening instrument called the Arizona Sexual Experience Scale.27 Screening questions were, “Can I ask if you have recently had any side effects from your medicines?” and “Have your medicines caused problems with your sexual functioning recently?” If patients respond “No” to both screening questions, there is little chance of finding sexual dysfunctions after further exploration. When patients respond “Yes” to the screening questions, sexual dysfunction and the possible burden should be explored in order to judge the necessity for further clinical guidance or intervention.

When sexual side effects are present, it is important to know which are present and what the burden may be for the patient in the context of desired clinical effects. Treatment history and available treatment alternatives should be included in discussion with the patient about possible consequences.

Possible Solutions for Sexual Side Effects of Antipsychotics

Education of the Patient

Some patients experience sexual side effects but do not consider the effects to be a problem. In such cases, clinicians may find that explaining the nature of the side effects is sufficient. Particularly when men experience a diminished volume of ejaculation—sometimes becoming the cause of worry—the problem may be well addressed by explaining that it is a reversible treatment-related effect. Studies comparing sexual side effects after a short treatment period, such as 6 weeks, show the same frequencies of sexual side effects in comparison to long-term treatment periods over many years.12,21 Since tolerance for sexual side effects appears not to develop, it would not be helpful to wait for the spontaneous recovery of sexual side effects. Although tolerance is not to be expected, sexual side effects typically appear to be reversible. One exception is priapism, which should be considered an emergency; referring to a specialized center for immediate treatment may prevent irreversible erectile dysfunction.

When sexual side effects are reported, patients should be informed about the nature of these effects and treatment options. Some patients will tend to accept these side effects; others will want to explore alternative treatment options.

Dose Reduction

Some studies suggest that sexual side effects may be related to dosage.26 For this reason, as long as treatment remains effective, lowering the dosage could be considered for patients experiencing sexual side effects.

Switching Strategies in General

Often dosage lowering is not possible as the treatment may decrease in efficacy. Depending on what dimension of sexual performance may be involved, switching to a less sedative antipsychotic (reduction of sexual desire) or switching to an antipsychotic with less α1-blocking properties (dry ejaculation) could be considered.5,7,13

Switching Strategies from a Prolactin-Elevating to a Prolactin-Sparing Antipsychotic

Antipsychotics may influence many dimensions of sexual functioning, and switching to a less prolactin-elevating antipsychotic may be considered. Prolactin elevation may be an expression of dopamine blocking in the pituitary gland. In most antipsychotics, this is closely correlated to dopamine blocking in other brain areas. Switching from a prolactin-elevating antipsychotic to a prolactin-sparing antipsychotic may diminish several dimensions of sexual side effects. This switch strategy was investigated in four studies.26,28-30 In a randomized, double-blind study, switched patients with sexual dysfunction were treated with classical antipsychotics (n=27) or risperidone (n=12, 4 mg/day) versus fluphenazine (n=9, 12.5 mg/day) or quetiapine (n=6, 400 mg/day).28 Patients switching to quetiapine reported a significant improvement in sexual performance (improvement of arousal and a trend in improvement of libido).

In a study of 20 female patients with sexual side effects treated with risperidone (mean dosage=3.5 mg/day), the patients were switched to olanzapine (mean dosage=9.1 mg/day).29 The switch resulted in a reduction of reported sexual side effects, from 50% to 30%. In an open, randomized study, 50% of patients treated with risperidone (n=29) or classical antipsychotics (n=25) were switched to olanzapine (mean dosage=12.8 mg/day).30 Patients switched to olanzapine (n=27) reported a significant reduction in sexual side effects. The findings are similar to a naturalistic follow-up study evaluating sexual dysfunction in 18 patients with sexual side effects treated with a prolactin-elevating antipsychotic.26 After the patients were switched to a prolactin-sparing antipsychotic, 14 out of 18 patients found that their sexual side effects had disappeared.

Treatment with a Dopamine Agonist

As dopamine blocking appears to be important for antipsychotic action, treatment with a dopamine agonist for sexual side effects seems counterintuitive. In theory, dopamine agonists may be effective in the treatment of sexual side effects, but they may also increase psychotic symptoms. Dopamine agonists that have been studied and shown to be effective are bromocriptine (5.0–7.5 mg/day) and cabergoline (.125–.250 mg/week to 2 mg/week).31-33 These studies suggest that dopamine agonists may be safe, but, as expected, some patients experienced an increase in psychotic symptoms. Although not studied in patients treated with antipsychotics, apomorfine (a short-acting dopamine agonist) could also be a useful treatment alternative. It is important to note that treatment with dopamine agonists implies experimental off-label use of these medications.

Treatment with a Phosphodiesterase Inhibitor

Several phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil) are marketed for treatment of erectile dysfunction. Case reports suggest that phosphodiesterase inhibitors may improve erectile dysfunction in treatment with antipsychotics. Recently, a double-blind, crossover, placebo-controlled study showed that sildenafil was effective and well-tolerated in the treatment of antipsychotic-induced erectile dysfunction.34

Conclusion

Sexual dysfunctions related to treatment with antipsychotics are studied infrequently. Most are open studies using miscellaneous designs and questionnaires.

Although <10% of patients spontaneously mention sexual dysfunctions, in response to structured questionnaires 40% to 60% of patients reported experiencing sexual dysfunctions that they attributed to the use of classical antipsychotics or risperidone. Although studies have found differing results, reduction of desire and orgasm disturbances are found in men and women in approximately the same frequency. In addition, comparative studies are rare; it appears that prolactin-sparing antipsychotics induce sexual dysfunction less frequently. In randomized studies of olanzapine and quetiapine versus risperidone, prolactin-sparing effects of olanzapine and quetiapine are associated with significantly less sexual dysfunction.

Serum prolactin elevation and dopamine blocking may be important factors in inducing sexual dysfunctions. Additional studies and studies with standardized assessment methods that compare antipsychotics and their tendency to induce sexual side effects are needed. Studies on the pathogenetic mechanisms and the long-term effects on social behavior and health risks are needed as well.

Although particular studies show that sexual side effects are important to patients and may influence compliance, other studies show that both patients and clinicians are reluctant to discuss such effects.4,10,35 Clinicians should actively query for antipsychotic side effects, in particular sexual side effects, to give optimal guidance. A majority of patients appreciate when clinicians systematically ask for side effects, including sexual side effects. Dose reduction or switching to a prolactin-sparing antipsychotic is effective in reducing sexual side effects. In some cases, adding bromocriptine, amantadine, apomorfine, or another dopamine agonist may be an alternative. For patients predominantly experiencing erectile dysfunction, phosphodiesterase inhibitors may be a treatment option. PP

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