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Recognition and Management of Neuroleptic Malignant Syndrome

Richard C. Christensen, MD, MA

Focus Points

Neuroleptic malignant syndrome (NMS) is a potentially life-threatening condition that has been described as a drug-induced hyperthermia.

NMS may be precipitated by either the use of neuroleptics or the abrupt withdrawal of medications used to treat Parkinson’s disease.

The differential diagnosis of NMS includes a wide range of disorders that present with fever. The differential diagnosis can be narrowed to NMS by the associated symptoms of rigidity, autonomic dysfunction, and mental status changes.

The focus of treatment is early recognition, prompt discontinuation of the neuroleptic, and supportive medical measures. In some cases, the use of pharmacologic interventions (eg, benzodiazepines, dopaminergic agonists, and/or antispasmodics) may be efficacious.

Abstract

What is neuroleptic malignant syndrome (NMS)? How does the clinician identify the constellation of risk factors and clinical signs associated with it, in order to initiate early and timely intervention? NMS is a potentially life-threatening condition that has typically been described as a drug-induced hyperthermia. Fortunately, a decline in the mortality rate of NMS is reported to be associated with early recognition, abrupt discontinuation of the causative neuroleptic medication, and the institution of supportive care. The widespread use of neuroleptics within the community, as well as recent reports of this syndrome occurring in those abruptly withdrawn from medications used to treat Parkinson’s disease, makes it important for the primary care provider and psychiatrist to understand the early signs of clinical presentation, differential diagnosis, and initial management of NMS.

Introduction

Primary care physicians (PCPs) are often called upon to evaluate psychiatric patients maintained on neuroleptic medications who have developed a fever or are deteriorating physically. Additionally, PCPs and psychiatric consultants may need to administer neuroleptics to nursing home residents to control agitation or psychosis within the context of dementia. They may also encounter new-onset complications in those abruptly withdrawn from medications used to treat Parkinson’s disease. Thus, the widespread use of neuroleptics and anti-Parkinsonian medications within this community makes it important for providers to understand the early signs of the clinical presentation, differential diagnosis, and initial management of neuroleptic malignant syndrome (NMS).

NMS is a potentially life-threatening form of drug-induced hyperthermia.1 Although it is not a common side effect of antipsychotic and dopaminergic blocking agents (ie, neuroleptics), it is by no means rare. Estimates of the incidence of NMS developing in those exposed to neuroleptic medication range from 0.02% to 1.8%.2 Even in the face of therapeutic efforts, mortality can be a direct outcome of NMS. Fortunately, this rate has shown a significant decline in the past 2 decades due to the development of a significant body of literature pertaining to the early diagnosis and management of this potentially lethal syndrome.3-5 Nonetheless, there is evidence to support the view that this entity frequently goes unrecognized and underdiagnosed, especially in those treated with non-antipsychotic causative agents.6

Clinical Presentation

NMS is a clinical syndrome, though its precise mechanism of action is unknown. It may be the result of an extensive blockade of dopamine receptors or a rapid decrease in the dopamine activity in the nigrostriatal pathways, which affects the thermoregulatory centers in the anterior hypothalamus.7,8 This dysregulation can lead to a generalized, systemic hypermetabolic state if a diagnosis of NMS is not considered and a causative agent identified.

The onset of NMS has classically been described as evolving over a period of 24–72 hours.4 However, its diagnosis is generally one of exclusion and is based upon the classic symptom cluster of mental status changes, autonomic instability, muscular rigidity, and hyperthermia. Patients may also manifest with oculogyric crises, trismus, opisthotonos, and/or a Babinski sign.8 Laboratory findings are usually significant for a nonspecific leukocytosis and an elevated serum creatine phosphokinase (CPK). CPK elevation, secondary to rhabdomyolysis, is present in ≤95% of cases. In some rare situations, CPK can be as high as 2,000 times normal values.9 In progressive cases, myoglobinuria may be present, which can lead to acute renal failure if left untreated.10 Table 1 outlines the diagnostic criteria for identifying NMS, as contained within the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).11

Recently, investigators have identified heterogeneity among reported cases and have drawn distinctions between incipient and fulminant syndromes. These investigators argue for a spectrum concept of NMS and a more flexible diagnostic criteria than the one currently put forth by the DSM-IV.12,13 In fact, recent studies have identified what may prove to be a temporal sequence in the progression of the full-blown syndrome.14 Recognition of these early signs of NMS by the primary care physician and/or psychiatrist could lead to a significant reduction in the morbidity and mortality associated with this idiosyncratic, but potentially fatal, drug-induced reaction.4

A published review of 153 case reports of NMS analyzed the sequential pattern of the four predominant classes of symptoms which characterize this syndrome: mental status changes, rigidity, hyperthermia, and autonomic instability.15 Mental status changes (eg, new-onset confusion or disorientation) or muscular rigidity (eg, severe cogwheeling  or “lead-pipe” rigidity in the neck or extremities) preceded the development of hyperthermia and autonomic instability in >83% of the cases analyzed. Mental status changes, muscle rigidity, and autonomic dysfunction followed by hyperthermia occurred sequentially in >70% of the reports. Other researchers have corroborated that mental status changes (especially confusion) and extrapyramidal symptoms usually precede other signs of NMS and that temperature elevation may represent a rather late sign of a potentially fulminant state.16 A clinician capable of recognizing an incipient or developing case of NMS is well prepared to initiate timely and appropriate treatment.

Risk Factors

Potential risk factors have been identified as previous episodes of NMS, psychomotor agitation, dehydration, a rapid increase of neuroleptic medication, and parenteral routes of administration (Table 2).17 Although conventional and atypical antipsychotics (ie, both second- and third-generation antipsychotics) are the most common agents causing NMS, any agent which possesses dopaminergic antagonistic actions can be implicated, including the antiemetics prochlorperazine and metoclopramide. There have also been a number of reports identifying the development of this disorder in those who have been abruptly withdrawn from the Parkinson’s disease medications L-dopa and amantadine.9,18

 

Differential Diagnosis

Securing the diagnosis of NMS is frequently challenging and clinically complex. The differential diagnosis is narrowed considerably by focusing primarily upon those disorders in which endogenous heat generation is secondary to a central thermal dysregulaton (Table 3). However, as has been previously noted, early or developing cases of NMS may not always be accompanied by a rise in core body temperature. Therefore, it is critically important that clinicians pay close attention to what may be early clinical signs of evolving NMS (eg, mental status changes such as confusion or rapidly developing muscular rigidity) as they proceed with a comprehensive medical and laboratory workup. The following discussion primarily focuses on disorders of thermoregulation which share common clinical features with NMS.19

 

Systemic Disorders

A number of systemic disorders can mimic the presentation of NMS; thus, a careful evaluation of the causes of the intercurrent fever is warranted in order to achieve diagnostic clarification. Entities that share a constellation of similar symptoms with NMS (eg, mental status changes, autonomic instability, and fever) include infections, endocrinopathies, extrapyramidal symptoms with fever, autoimmune disease, and heatstroke. In addition, drug reactions may have similar signs, specifically malignant hyperthermia secondary to the use of anesthetic agent, toxicity induced by anticholinergic agents, serotonin syndrome, and withdrawal from alcohol.8

Although the specific distinguishing features of each of these disorders is beyond the scope of this paper, it should be noted that rigidity is an important criterion distinguishing NMS from many systemic disorders. A focused history taken from collateral sources, combined with a physical examination and careful neurological evaluation, is the initial clinical starting point. However, a complete blood cell count with differential to evaluate for leukocytosis; total CPK; a comprehensive metabolic profile (in which elevated lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase may suggest possible myonecrosis); and urinalysis to investigate the presence of myoglobinuria would all also be helpful in narrowing the diagnosis to NMS.

Primary Brain Disorders

Central nervous system disorders can frequently be difficult to distinguish from NMS, especially when the presenting signs are behavioral in nature.4 The most common disorders that can produce a clinical picture that looks like NMS are tumors, abscesses, cerebral vascular accidents, traumatic brain injury, seizures, and infections (eg, human immunodeficiency virus, postinfectious encephalomyelitis, and viral encephalitis).8 In addition, the evolution of a psychotic syndrome into a state of lethal catatonia can lead to exhaustion, stupor, hyperthermia, and possibly death. Again, a careful history, physical and neurological exams, and lab studies are all indicated, along with the use of imaging studies and lumbar puncture when clinically appropriate. Table 4 lists the clinical signs and symptoms which differentiate the five most common etiologies for hyperthermic states.19

 

Initial Management

In situations where NMS is not identified, goes unrecognized, or is misdiagnosed (thereby delaying timely intervention), the risk of mortality may increase. Once identified, treatment of the syndrome must commence immediately. The initial and most efficacious treatment for NMS is based squarely upon early recognition, discontinuation of the neuroleptic when this is the causative agent, and the provision of supportive care when indicated. Fluid replacement, reduction of temperature, and support of cardiac, respiratory, and renal functions are all essential clinical measures which ought to be instituted by the treating physician.20 In one review of 65 cases involving oral neuroleptics and treated only with supportive measures, the recovery time was 9.6±9.1 days. Twenty-three percent recovered in 48 hours, 63% by the end of 1 week, and 97% by the end of 1 month. Ten percent of the 256 cases reported in the literature from 1980–1987 ended in death.21 The most common immediate causes of death associated with NMS are cardiac and respiratory arrest, arrhythmias, pulmonary emboli, disseminated intravascular coagulation, and myoglobinuric renal failure.

Medication interventions can involve the use of benzodiazepines, dopamine agonists (eg, bromocriptine or amantadine), and/or muscle relaxants (eg, dantrolene). Several of these medications have shown promise in the successful treatment of NMS, although there remains a paucity of controlled, prospective studies to clearly substantiate their efficacy.

Bromocriptine, a centrally acting dopamine agonist, has been shown to provide relief of rigidity and other symptoms of blockade in a number of case reports. Dosages range from 2.5–10 mg TID orally. Amantadine, also a dopamine agonist, is used orally in dosages of 100 mg BID to 100 mg QID. Dantrolene, a direct muscle relaxant, can be used alone or in combination with bromocriptine in dosages of 50–200 mg orally or 0.8–1.0 mg/kg intravenously every 6 hours. Benzodiazepines may be effective in milder cases of NMS22 and electroconvulsive therapy in more prolonged or resistant cases.23 The duration of treatment ought to be determined by the improvement in the clinical status of the patient; however, ≥2 weeks has been suggested by certain clinicians.8

Upon recovery from NMS, the patient who has a chronic psychotic disorder (eg, schizophrenia) can be rechallenged with a neuroleptic agent; however, the recurrence rate has been estimated to be close to 30%.24 It has been suggested that 2 weeks from the resolution of NMS should elapse prior to rechallenge, and the use of a low-dose atypical antipsychotic should be considered. Close vigilance on the part of the prescribing physician for signs of recurrent and early NMS is obviously warranted.

Conclusion

It can be argued that over the course of the last decade, early recognition of incipient cases of NMS by clinicians and prompt withdrawal of the neuroleptic has led to a decline in the mortality and morbidity associated with this potentially lethal syndrome. Although data do not yet exist that clearly substantiate a temporal pattern of symptoms in NMS, current clinical evidence suggests that a predictable progression of symptoms (eg, mental status changes, muscle rigidity, autonomic instability, and hyperthermia) may be identified in many cases. Enhanced awareness of these early signs and greater vigilance on the part of physicians who treat patients receiving agents that affect dopaminergic activity may well provide the opportunity to abort emerging cases of NMS. Furthermore, early recognition of the syndrome and prompt discontinuation of the neuroleptic agent with patient-tailored supportive and pharmacologic interventions can avert a life-threatening medical crisis. PP

References

1. Gurrera RJ. Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia? Clin Neuropharmacol. 2002;4:183-193.

2. Adityanjee, Aderibigbe YA, Mathews T. Epidemiology of neuroleptic malignant syndrome. Clin Neuropharmacol. 1999;3:151-158.

3. Bristow MF, Kohen D. Neuroleptic malignant syndrome. Br J Hosp Med. 1996;8:517-520.

4. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993;1:185-202.

5. Caroff SN, Rosenberg H, Mann SC, Campbell EC, Sullivan KA. Neuroleptic malignant syndrome in the critical care unit. Crit Care Med. 2002;11:2609.

6. Ong KC, Chew EL, Ong YY. Neuroleptic malignant syndrome without neuroleptics. Singapore Med J. 2001;2:085-088.

7. Northoff G. Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology. J Neural Transm. 2002;12:1453-1467.

8. Fait ML, Wise MG, Jachna JS, et al. Psychopharmacology. In: Wise MG, Rundell JR, eds. The American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry: Psychiatry in the Medically Ill. 2nd ed. Washington, DC: American Psychiatric Publishing; 2002:939-988.

9. Mann SC, Caroff SN, Keck PE, Lazarus A. Neuroleptic Malignant Syndrome and Related Conditions. 2nd ed. Washington, DC: American Psychiatric Press; 2003:1-44.

10. Nishioka Y, Miyazaki M, Kubo S, Ozono Y, Harada T, Kohno S. Acute renal failure in neuroleptic malignant syndrome. Ren Fail. 2002;4:539-543.

11. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

12. Velamoor VR, Swamy GN, Parmar RS, Williamson P, Caroff SN. Management of suspected neuroleptic malignant syndrome. Can J Psychiatry. 1995;9:581-584.

13. Reeves RR, Torres RA, Liberto V, Hart RH. Atypical neuroleptic malignant syndrome associated with olanzapine. Pharmacotherapy. 2002;5:641-644.

14. Velamoor VR, Norman RM, Caroff SN, Mann SC, Sullivan KA, Antelo RE. Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis. 1994;3:168-173.

15. Modestin J, Toffler G, Drescher JP. Neuroleptic malignant syndrome: results of a prospective study. Psychiatry Res. 1992;3:251-256.

16. Addonizio G, Susman VL. Neuroleptic Malignant Syndrome: A Clinical Approach. St. Louis, MO: Mosby Press; 1991.

17. Viejo LF, Morales V, Punal P, Perez JL, Sancho RA. Risk factors in neuroleptic malignant syndrome. A case-control study. Acta Psychiatric Scand. 2003;1:45-49.

18. Serrano-Duenas M. Neuroleptic malignant syndrome-like, or dopaminergic malignant syndrome, due to levodopa therapy withdrawal. Clinical features in 11 patients. Parkinsonism Relat Disord. 2003;3:175-178.

19. Sternbach H. Serotonin syndrome: how to avoid, identify, and treat dangerous drug interactions. Current Psychiatry. 2003;5:15-23.

20. Hall KL, Taylor WH, Ware MR. Neuroleptic malignant syndrome due to olanzapine. Psychopharmacol Bull. 2001;3:49-54.

21. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull. 1988;1:25-29.

22. Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q. 2001;4:325-336.

23. Fink M. Convulsive therapy: a review of the first 55 years. J Affect Disord. 2001;1-3:1-15.

24. Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry. 1989;8:295-298.

 

 


 

Dr. Christensen is associate professor of psychiatry and director of the Community Psychiatry Program at the University of Florida College of Medicine in Jacksonville.

Disclosure: The author reports no financial, academic, or other support of this work.

Please address all correspondence to: Richard C. Christensen, MD, MA, 655 West 8th St, Jacksonville, FL 32209; Tel: 904-244-3990; Fax: 904-244-3455; E-mail: richkchris@aol.com.

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Depression, Antidepressants, and Human Sexuality

Richard Balon, MD

Return

Primary Psychiatry. 2007;14(2):42-44,47-50

Dr. Balon is professor in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University School of Medicine in Detroit, Michigan.

Disclosure: Dr. Balon is on the speaker’s bureau of GlaxoSmithKline; and receives research support from Janssen.

Please direct all correspondence to: Richard Balon, MD, Wayne State University, University Psychiatric Center-Jefferson, 2751 E. Jefferson, Suite #200, Detroit, MI 48207; E-mail: rbalon@wayne.edu.


Focus Points

• Sexual dysfunction occurs frequently during the course of depression.
• Sexual dysfunction during the treatment of depression may have multiple causes, such as depression itself, medical illness, and/or medications, including antidepressants.
• All antidepressants are associated with sexual dysfunction, though the prevalence of sexual dysfunction may differ among antidepressants.
• The strategy to manage sexual dysfunction associated with antidepressants must be carefully and appropriately selected and individualized.


Abstract

Human sexual functioning can be profoundly negatively affected by depression, anxiety, medications, and other factors. The estimates of sexual dysfunction associated with depression (eg, decreased libido) vary, but may reach up to 70%. The estimates of sexual dysfunction associated with antidepressant treatment also vary significantly, depending on the antidepressant and the study. It has been suggested that some antidepressants, such as bupropion, mirtazapine, and nefazodone, are associated with sexual dysfunction less frequently. There is evidence supporting the existence of sexual dysfunction as a frequent side effect of antidepressants, but the evidence is not robust to make a definite conclusion about individual differences between antidepressants. Management of sexual dysfunction associated with antidepressants is a complicated clinical problem with several management strategies available. This article reviews the evidence for sexual dysfunction during depression and sexual dysfunction associated with antidepressants. Management strategies of sexual dysfunction associated with antidepressants are also reviewed.

Introduction

At the beginnings of modern-era psychopharmacology, side effects of medications were an unpleasant reality and the evaluation of medications focused mostly on their efficacy. As psychopharmacology has become more refined, the focus on identifying side effects and efforts to minimize them have become more prominent. The supposedly more refined and better-tolerated medications are void of the bothersome side effects of older medications. A good example is the group of selective serotonin reuptake inhibitors (SSRIs). They are not associated with sedation and a host of anticholinergic symptoms. However, the new medications may have their own problems. Examples include the newer antipsychotics associated with a host of metabolic side effects, and, again, the SSRIs. As noted in a meta-analysis by Steffens and colleagues,1 patients taking SSRIs experienced significantly more gastrointestinal problems and sexual dysfunction, whereas treatment with the older tricyclic antidepressants (TCAs) produced significantly more complaints of sedation, dizziness, and anticholinergic symptoms.

Sexual side effects have become one of the more prominent groups of side effects associated with antidepressants. There are several reasons for this relative prominence and the recent increase in interest in these side effects. First, sexual side effects of antidepressants are fairly frequent and probably more frequent with the SSRIs than with the older antidepressants.1 Second, with the refinements of psychopharmacologic agents, more attention is being paid to patient quality of life. Good, unimpaired sexual functioning is considered to be a part of good quality of life. Third, as with other side effects, sexual side effects of antidepressants became an issue in marketing “wars” of antidepressant makers.

Sexual side effects of antidepressants are a clinical reality. As one goal for clinicians in treating depressed patients should be a good quality of life accompanied by unhindered and satisfactory sexual functioning, one may assume that clinicians need to focus, among others, on minimizing the sexual side effects of antidepressants. Although this is certainly true, the situation is more complicated. Sexual dysfunction may have many causes, such as mental illness (especially depression), medical illness, psychosocial factors, medications (psychotropic and non-psychotropic), substances of abuse, and others. This article focuses on sexual dysfunction in depressed patients and during treatment with antidepressants. Possible management approaches are also discussed.

Depression and Human Sexuality

Depression has a profound effect on various body functions. Sexual dysfunction, especially decreased sexual desire, has been frequently reported during depression. For example, Casper and colleagues2 reported that 77% of patients with bipolar depression and 72% of patients with unipolar depression reported loss of libido. Interestingly, the increase in severity of depression was associated with greater loss of libido. However, as pointed out in some recent reviews,3,4 sexual dysfunction associated with depression is not limited to decreased libido. Impaired arousal and orgasm may also occur during depression.5,6 Nevertheless, most experts and clinicians would agree that decreased libido is probably the most frequent sexual dysfunction associated with depression.

There are several caveats regarding the prevalence of sexual dysfunction associated with depression. One is that an exact estimate of prevalence of sexual dysfunction during depression is very difficult and probably impossible to establish at the present time. Sexual dysfunction is reportedly quite prevalent in the general population. In a study by Laumann and colleagues,7 the prevalence of sexual dysfunction in a national probability sample was 43% among women and 31% among men. Interestingly, in a study set in four general practices in England, 41% of women and 34% of men reported having a current sexual problem.8 In another study from Britain,9 53.8% of women and 34.8% of men who had at least one heterosexual partner in the previous year reported at least one sexual problem lasting at least 1 month. These numbers seem fairly consistent, but are they realistic? How do these numbers relate to the estimates of sexual dysfunction associated with depression? Most of the estimates of sexual dysfunction come from epidemiologic studies known for their methodologic problems and overestimates.

The second caveat is that the current definition of sexual dysfunction is unclear and imprecise. Most studies are unclear about the duration of sexual dysfunction, its intensity, possible fluctuation of intensity, course, and other issues. The study mentioned above by Mercer and colleagues9 illustrates how just one of these definitional issues can play havoc in our estimates of sexual dysfunction. As mentioned, the authors reported that 53.8% of women and 34.8% of men had at least one sexual problem lasting at least 1 month. However, persistent sexual problems lasting at least 6 months in the previous year were less prevalent (15.6% of women and 6.2% of men).

The third caveat is that sexual dysfunction in depressed and non-depressed people may have more than one cause. Sexual dysfunction has been reported with many mental (eg, anxiety, substance abuse) and physical disorders (eg, cardiovascular, neurologic, endocrine), which are frequently comorbid with depression. Interpersonal conflicts may also lead to impairment of sexual functioning. In addition, many medications other than antidepressants may cause sexual dysfunction.10 These factors are usually not accounted for in various epidemiologic estimates of sexual dysfunction in the general population or in estimates of sexual dysfunction associated with depression. However, they need to be considered in the clinical situation when addressing sexual dysfunction associated with antidepressants.

Finally, according to a survey in the United Kingdom, 75% of depressed people (versus 70% of the total sample) feel that having a good sex life is fairly or very important (D.S. Baldwin, DM, FRCPsych, as cited in Ferguson11). This observation has an important implication for the treatment of sexual dysfunction associated with antidepressants; good sexual functioning should be one of the treatment goals.

Impairment of sexual functioning clearly occurs as a part of depressive and other mental illness symptomatology. The estimates of its prevalence vary, but may actually be >50%,2,6 probably even 70%.2

Antidepressants and Human Sexuality

Cases of sexual dysfunction associated with TCAs and monoamine oxidase inhibitors (MAOIs) have been reported almost since their introduction.12,13 For various reasons, sexual side effects associated with the older antidepressants were not a prominent clinical issue during the early era of clinical psychopharmacology. Other side effects of these medications were considered more serious, and the quality of certain aspects of life, including sexual function, was not the main focus (if a focus at all) of clinical research. However, as the new, more tolerable antidepressants were developed, interest in sexual dysfunction associated with antidepressants gradually increased. The newer antidepressants started to be used for other indications previously not frequently if ever treated with antidepressants (eg, anxiety disorders), and for less severe conditions (eg, dysthymia). This may have, paradoxically, led to a greater attention to various side effects, including sexual dysfunction.10

The original estimates of sexual dysfunction with some of the new antidepressants were clearly unrealistic. This was probably due to the fact that many of the reports of sexual dysfunction associated with antidepressants were based on spontaneous reporting and not on proactive evaluation of these side effects. For example, the estimate of sexual dysfunction associated with fluoxetine cited in the Physician’s Desk Reference14 volumes during the 1990s was 1.9%. However, various studies demonstrated already during the 1990s that the rates of sexual dysfunction with fluoxetine15,16 and other old and new antidepressants17 are much higher. Newer studies yielded fairly high estimates of sexual dysfunction associated with antidepressants. For example, Montejo and colleagues18 reported the overall incidence of sexual dysfunction with various antidepressants to be 59.1%, with some of them being as high as 72.7% (citalopram) and 70.0% (paroxetine), and some as low as 8.0% (nefazodone) or 3.9% (moclobemide). Bupropion was not evaluated in this study. The antidepressants with the lowest risk of sexual dysfunction in a study by Clayton and colleagues19 were bupropion (22%) and nefazodone (28%), while the SSRIs mirtazapine and venlafaxine were associated with higher rates of sexual dysfunction (36% to 43%). Both of these studies used fairly large population samples but had their share of methodologic problems (eg, lack of baseline evaluation of sexual dysfunction). Nevertheless, the results of these and many other studies suggest that sexual dysfunction is a fairly frequent side effect of antidepressants. Since the early 1990s, hundreds of articles reported the rates of sexual dysfunction associated with antidepressants in various observational, epidemiologic, and comparative studies. A review of all these studies is beyond the scope of this article.

There were also numerous review articles summarizing sexual dysfunction associated with antidepressants.20-30 Most of the authors agree that sexual dysfunction is a relatively frequent side effect of many of the antidepressants in common use today and that the rates of sexual dysfunction are probably higher than those reported by antidepressant manufacturers.26 Some suggest that the likelihood of developing and maintaining sexual dysfunction is determined by the balance of serotonergic, noradrenergic, and dopaminergic properties of individual antidepressants.30

Selective Serotonin Reuptake Inhibitors

The estimates of prevalence of sexual dysfunction associated with antidepressants varies. Most studies suggest that between 30% and 70% of patients treated with SSRIs may experience some form of sexual dysfunction,26,30 most frequently anorgasmia.

Tricyclic Antidepressants

The estimates of sexual dysfunction associated with TCAs vary more, as it reached >90% in some studies (eg, with clomipramine).31 To be fair, it is important to note that this31 was not a study of depressed patients, but rather of patients with obsessive-compulsive disorder. The type or character of sexual dysfunction(s) associated with TCAs seems to vary a bit more, with erectile dysfunction being probably the most frequent, but delayed ejaculation occurring quite frequently with clomipramine, a predominantly serotonergic TCA. Amitriptyline and doxepin may have a lower prevalence of sexual dysfunction than other TCAs.30 However, the rates of sexual dysfunction associated with TCAs (and MAOIs) are more difficult to estimate as these antidepressants have been studied much less with regard to sexual dysfunction. During their heydays, as noted, the focus was on more serious side effects, and there have not been many studies on these drugs lately.

Monoamine Oxidase Inhibitors

Sexual dysfunction associated with MAOIs does not reach >40% in most studies,30 with moclobemide-associated sexual dysfunction occurring least frequently (eg, 3.9%18). Not much is known about the actual prevalence of sexual dysfunction associated with the recently approved transdermal selegiline.

Newer Antidepressants

Some of the newer antidepressants, such as bupropion, reboxetine (not available in the United States), and mirtazapine, seem to be associated with sexual dysfunction substantially less frequently. Nefazodone and trazodone are also rarely associated with sexual dysfunction, though trazodone has been reported infrequently as culprit in cases of priapism.32 Venlafaxine seems to be the agent most frequently associated with sexual dysfunction in the group of newer antidepressants. Finally, duloxetine may have lower rates of sexual dysfunction.33 However, not many studies addressing sexual dysfunction associated with this antidepressant have been published and those published suggest rates between 40% and 50%.34

It is important to note that sexual dysfunction has been reported with all antidepressants used in the treatment of anxiety disorders27 and in healthy volunteers exposed to fluvoxamine (up to 35%35; sexual dysfunction due to antidepressants versus sexual dysfunction due to mood disorder). Antidepressants with possibly lower rates of associated sexual dysfunction are highlighted in Table 1.

Montgomery and colleagues27 carefully examined and critiqued the literature evidence on the existence of sexual dysfunction associated with antidepressants as well as its incidence and prevalence. They concluded that the existing literature confirms sexual dysfunction as a possible side effect of all antidepressants, but it is not sufficiently robust to support claims for differences in the incidence of drug-induced sexual dysfunction between existing antidepressant therapies. They also pointed out several difficulties in the process of determining the rates of antidepressant-induced sexual dysfunction. In addition to the previously discussed difficulties in establishing the “baseline” prevalence of sexual dysfunction in the general population and the greater risk of sexual dysfunction in depression (and anxiety) disorders, these difficulties include the fact that reporting on sexual dysfunction is prone to under-reporting unless careful attention is paid to the method of data collection (spontaneous reporting versus systematic collection); the fact that human sexual behavior is subject to many disparate social and cultural influences, which may vary with time, place, ethnic group, and social class; and that all studies on sexual dysfunction associated with antidepressants had methodologic flaws such as failure to use validated rating scales, failure to include a baseline assessment and/or placebo control group, and lack of randomization and/or blinding.

Management of Sexual Dysfunction Associated with Antidepressants

Management of sexual dysfunction associated with antidepressants begins during the initial evaluation of a patient considered for medication treatment. A good initial evaluation should include a comprehensive sexual history and evaluation of current and premorbid sexual functioning. Gitlin20 and Clayton36 suggest that the evaluation should also include a medical and psychiatric history, identification of substances that may contribute to sexual dysfunction (medications, alcohol, illicit substances), the potential interpersonal context of the sexual dysfunction, endocrine measures if and as indicated (eg, thyroid hormones, testosterone), and a targeted physical examination (including neurologic and genitourinary exam as indicated). As mentioned previously, many studies of sexual dysfunction associated with medications had a major methodologic flaw, which is also a clinical flaw; namely, lack of a baseline evaluation. An experienced clinician is aware of the fact that one cannot always rely on the patient’s memory. Asking the patient 4 weeks later whether he or she had any difficulties with erection or orgasm is not the best way to collect reliable information. The initial evaluation should also include an acknowledgment of the possibility of sexual dysfunction associated with medications and communication of this possibility to the patient.

There may be barriers or obstacles to an appropriate evaluation of sexual functioning. Patients may be hesitant to communicate intimate problems or may have misconceptions about adequate sexual functioning. Thus, questioning about sexual functioning should be sensitive but straightforward and focused. Questions such as “How is your sex life?” are not very helpful. It is better to ask specifically about sexual desire, arousal, and experience of orgasm. Interestingly, physicians themselves may be a barrier to a good evaluation of sexual functioning, as they may feel uncomfortable with the topic or may mistakenly expect patients’ discomfort with this topic. Training in communication skills may help in sexual history taking.37 Physicians of certain specialties (eg, urologists) are more likely to address sexual problems than others (eg, general practitioners).37 Urologists together with psychiatrists and gynecologists are more concerned with sexual history taking compared to other disciplines.38 Clayton36 suggests that a major barrier to appropriate assessment could be the failure to use an adequate and appropriate assessment tool (gender specific, nonintrusive, able to separate illness form medication effects, addressing phase-specific function, brief, able to monitor changes over time, etc). She recommends several instruments such as the Arizona Sexual Experience Scale,39 the Changes in Sexual Functioning Questionnaire–Clinical Version,40 the Derogatis Interview for Sexual Functioning–Short Report,41 and the Rush Sexual Inventory (Table 2).42,43

A good baseline evaluation does not only provide the baseline data, but may also help the treating physician to select an appropriate sexual dysfunction management strategy. A patient who has never been treated with an antidepressant and for whom his or her undisturbed sexual functioning is quite important should probably be started on an antidepressant with a low incidence of sexual dysfunction. On the other hand, a patient who reports a history of sexual dysfunction with a particular antidepressant should probably not be started on that agent.

As with the prevalence and incidence of sexual dysfunction, there have been numerous published case reports, case series, and open studies as well as a few double-blind studies of management strategies. The review of their efficacy and risks is beyond the scope of this article. These studies have been critically summarized in many review articles20-30,44,45 and book chapters.10

The main strategies for antidepressant-induced sexual dysfunction can be found in Table 3. The first strategy is starting treatment with an antidepressant with a low prevalence of associated sexual dysfunction, such as bupropion, mirtazapine, and nefazodone (in some countries also moclobemide or reboxetine, neither available in the US). This strategy could be useful for sexually active, medication-naive patients. A second strategy is waiting for spontaneous remission of sexual dysfunction. This strategy requires a good deal of patience and a good doctor-patient relationship. The effectiveness is usually low. It has been reported that a substantial proportion of patients still report antidepressant-induced sexual dysfunction after several months of treatment with antidepressants.46 This strategy may be useful for patients with a low frequency of sexual activity. A third strategy is scheduling sexual activity around the dose of antidepressant, delaying daily medication intake after the sexual activity. This strategy may work for some of the short half-life antidepressants, but not much is known about its efficacy. A fourth startegy is reduction of dosage. This strategy may be especially useful in patients having other side effects as well.44 However, it may be risky. Patients may relapse if a subtherapeutic dose is reached. A fifth strategy is drug holidays. This strategy involves relatively brief interruption of treatment (eg, 2–3 days) with sexual activity scheduled for the end of this period of interruption. A variant of this approach is the partial drug holiday strategy, ie, lowering the dose of antidepressant for a brief period. This strategy poses several possible risks, such as relapse of depression, discontinuation syndrome in short half-life antidepressants, and encouragement of non-adherence.

A sixth strategy is switching to an antidepressant with a low rate of associated sexual dysfunction, such as bupropion, mirtazapine, and nefazodone (in some countries also moclobemide and reboxetine). This strategy has been described as one of the most effective ones. It should be used especially in relatively treatment-naïve patients (the first or second antidepressant, not the fifth medication that finally helped with depression). The possible risks include relapse of depression and/or emergence of new side effects with the new antidepressant.

A seventh strategy involves use of so-called antidotes or other medications to alleviate sexual dysfunction. The list of antidotes which have been reported includes amantadine, bethanechol, bromocriptine, bupropion, buspirone, cyproheptadine, dextroamphetamine, ephedrine, gingko biloba, granisetron, loratadine, methylphenidate, mirtazapine, nefazodone, neostigmine, pemoline, pramipexole, ropinirole, sildenafil, tadalafil, trazodone, vardenafil, and yohimbine. The usefulness of most of these antidotes has been reported in case reports or case series. As noted previously, according to Osler,47 when too many treatments are offered none is effective all the time and in all cases, and none is curative. The detailed review of efficacy, usefulness, and risk of each antidote is beyond the scope of this article. However, it is important to note that none of these substances has been Food and Drug Administration-approved for the treatment of sexual dysfunction associated with antidepressants.

There may be other adjuvant strategies theoretically helpful in managing antidepressant-associated sexual dysfunction. These include, for example, vacuum pumps and constriction rings. Some suggest behavioral strategies to improve sexual technique25 without clarification of what it really means. Others propose that adding strategies such as cognitive-behavioral therapy, vibrators, lubricants, or suggestion of mutual masturbation may be useful.29 However, the evidence for usefulness of these additional strategies is lacking.

Taylor and colleagues45 critically reviewed the evidence of effectiveness of management strategies for antidepressant-associated sexual dysfunction using the published randomized controlled trials. They found that the only strategies showing statistically significant improvement in sexual dysfunction compared to placebo were the addition of sildenafil, tadalafil, and bupropion (Table 4). (Here the evidence was not unequivocal.) They felt that the addition of sildenafil seems the most promising for erectile dysfunction. They did not find any trials assessing the benefits of psychological interventions, mechanical devices, or changes to antidepressant regimes such as dose reduction or drug holidays. They also pointed out that the currently available evidence is rather limited.

Werneke and colleagues30 suggested, as did many others, that substitution of a possible offending agent by using an alternative antidepressant with less impact on sexual function may be the first-line pharmacologic treatment. They also suggested that the use of antidotes should aim at reversing specific neurotransmitter activities known to mediate sexual dysfunction.

Conclusion

Sexual dysfunction associated with antidepressants remains a complicated clinical problem. It may occur in up to 70% of patients treated with some antidepressants. The estimates of rates of antidepressant-associated sexual dysfunction are complicated by numerous factors such as the occurrence of sexual dysfunction associated with depressive and other disorders, some physical illnesses, medications, and substances of abuse. Studies of sexual dysfunction in general, sexual dysfunction associated with depression, and sexual dysfunction associated with antidepressants have been marred by numerous methodologic issues (unclear definition, lack of baseline assessment, lack of validated assessment tools), which even further complicate the estimation of prevalence of sexual dysfunction associated with antidepressants.

Several management strategies for antidepressant-associated sexual dysfunction have been proposed. However, the evidence for their usefulness is limited. Most experts would recommend as first-line approaches either starting treatment with an antidepressant with a low prevalence of associated sexual dysfunction or switching to this kind of antidepressant if sexual dysfunction with another antidepressant develops. Evidence from literature suggests that adding sildenafil, tadalafil, or bupropion may be useful in some sexual dysfunction associated with antidepressants. The treatment of this side effect should be individualized and still remains a clinical art rather than a science. PP

References

1. Steffens DC, Krishnan KR, Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6(1):10-18.

2. Casper RC, Redmond DE Jr, Katz MM, Schaffer CB, Davis JM, Koslow SH. Somatic symptoms in primary affective disorders. Presence and relationship to the classification of depression. Arch Gen Psychiatry. 1985;42(11):1098-1104.

3. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry. 2006;67(suppl 6):33-37.

4. Williams K, Reynolds MF. Sexual dysfunction in major depression. CNS Spectr. 2006;11(8 suppl 9):19-23.

5. Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord. 1999;56(2-3):201-208.

6. Bonierbale M, Lancon C, Tignol J. The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Curr Med Res Opin. 2003;19(2):114-124.

7. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537-544. Erratum in: JAMA. 1999;281(13):1174.

8. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract. 1998;15(6):519-524.

9. Mercer CH, Fenton KA, Johnson AM, et al. Sexual function problems and help seeking behaviour in Britain: national probability sample survey. BMJ. 2003;327(7412):426-427. Erratum in: BMJ. 2003;327(7416):649.

10. Segraves RT, Balon R. Antidepressants and sexual dysfunction. In: Segraves RT, Balon R. Sexual Pharmacology: Fast Facts. New York, NY: W.W. Norton & Co.; 2003:45-72.

11. Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry. 2001;62(suppl 3):22-34.

12. Greenberg HR. Erectile impotence during the course of tofranil therapy. Am J Psychiatry. 1965;121:1021.

13. Simpson GM, Blair JH, Amuso D. Effects of anti-depressants on genito-urinary function. Dis Nerv Syst. 1965;26(12):787-789.

14. Physician’s Desk Reference. 51st ed. Montvale, NJ: Medical Economic Company; 1997:922.

15. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry. 1992;53(4):119-122.

16. Patterson WM. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry. 1993;54(2):71.

17. Balon R, Yeragani VK, Pohl R, Ramesh C. Sexual dysfunction during antidepressant treatment. J Clin Psychiatry. 1993;54(6):209-212.

18. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(suppl 3):10-21.

19. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.

20. Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry. 1994;55(9):406-413.

21. Harvey KV, Balon R. Clinical implications of antidepressant drug effects on sexual function. Ann Clin Psychiatry. 1995;7(4):189-201.

22. Segraves RT. Antidepressant-induced sexual dysfunction. J Clin Psychiatry. 1998;59(suppl 4):48-54.

23. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry. 2000;61(suppl 11):28-36.

24. Labbate LA. Sexual dysfunction and antidepressants. Primary Psychiatry. 2001;8(4)65-68.

25. Baldwin DS. Depression and sexual dysfunction. Br Med Bull. 2001;57:81-99.

26. Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM. Antidepressant-induced sexual dysfunction. Ann Pharmacother. 2002;36(10):1577-1589.

27. Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced dysfunction. J Affect Disord. 2002;69(1-3):119-140.

28. Baldwin DS. Sexual dysfunction associated with antidepressant drugs. Expert Opin Drug Saf. 2004;3(5):454-470.

29. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163(9):1504-1509.

30. Werneke U, Northey S, Bhugra D. Antidepressants and sexual dysfunction. Acta Psychiatr Scand. 2006;114(6):384-397.

31. Monteiro WO, Noshirvani HF, Marks IM, Lelliott PT. Anorgasmia from clomipramine in obsessive-compulsive disorder. A controlled trial. Br J Psychiatry. 1987;151:107-112.

32. Coccaro EF, Siever LJ. Second generation antidepressants: a comparative review. J Clin Pharmacol. 1985;25(4):241-260.

33. Hirschfeld RM, Vornik LA. Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine. J Clin Psychiatry. 2004;6(suppl 4):46-52.

34. Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol. 2004;14(6):457-470.

35. Nafziger AN, Bertino JS, Goss-Bley AI, Kashuba ADM. Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy. J Clin Psychiatry. 1999;60(3):187-190. Erratum in: J Clin Psychiatry. 1999;60(5):341.

36. Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin Psychiatry. 2001;62(suppl 3):5-9.

37. Tsimtsiou Z, Hatzimouratidis K, Nakopoulou E, Kyrana E, Salpigidis G, Hatzichristou D. Predictors of physicians’ involvement in addressing sexual health issues. J Sex Med. 2006;3(4):583-588.

38. Lewis CE. Sexual practices: are physicians addressing the issues? J Gen Intern Med. 1990;5(suppl 5):S78-S81.

39. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26(1):25-40.

40. Clayton AH, McGarvey El, Clavet GJ. The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull. 1997;33(4):731-745.

41. Derogatis LR. The Derogatis Interview for Sexual Functioning (DISF/DISF-SR): an introductory report. J Sex Marital Ther. 1997;23(4):291-304.

42. Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. Psychopharmacol Bull. 1997;33(4):755-760.

43. Rao D, Zajecka J, Skubiak T. The Modified Rush Sexual Inventory: preliminary psychometric findings. Psychiatry Res. 2005;137(3):175-181.

44. Zajecka J. Strategies for the treatment of antidepressant-related sexual dysfunction. J Clin Psychiatry. 2001;62(suppl 3):35-43.

45. Taylor MJ, Rudkin L, Hawton K. Strategies for managing antidepressant-induced sexual dysfunction: systematic review of randomised controlled trials. J Affect Disord. 2005;88(3):241-254.

46. Montejo-Gonzales AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23(3):176-194.

47. Segraves RT, Balon R. Antidepressants and sexual dysfunction. In: Segraves RT, Balon R. Sexual Pharmacology: Fast Facts. New York, NY: W.W. Norton & Co.; 2003:58.

 

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Depression, Antidepressants, and Human Sexuality

Richard Balon, MD
Primary Psychiatry. 2007;14(2):42-44,47-50

Dr. Balon is professor in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University School of Medicine in Detroit, Michigan.

Disclosure: Dr. Balon is on the speaker’s bureau of GlaxoSmithKline; and receives research support from Janssen.

Please direct all correspondence to: Richard Balon, MD, Wayne State University, University Psychiatric Center-Jefferson, 2751 E. Jefferson, Suite #200, Detroit, MI 48207; E-mail: rbalon@wayne.edu.


Focus Points

• Sexual dysfunction occurs frequently during the course of depression.
• Sexual dysfunction during the treatment of depression may have multiple causes, such as depression itself, medical illness, and/or medications, including antidepressants.
• All antidepressants are associated with sexual dysfunction, though the prevalence of sexual dysfunction may differ among antidepressants.
• The strategy to manage sexual dysfunction associated with antidepressants must be carefully and appropriately selected and individualized.


Abstract

Human sexual functioning can be profoundly negatively affected by depression, anxiety, medications, and other factors. The estimates of sexual dysfunction associated with depression (eg, decreased libido) vary, but may reach up to 70%. The estimates of sexual dysfunction associated with antidepressant treatment also vary significantly, depending on the antidepressant and the study. It has been suggested that some antidepressants, such as bupropion, mirtazapine, and nefazodone, are associated with sexual dysfunction less frequently. There is evidence supporting the existence of sexual dysfunction as a frequent side effect of antidepressants, but the evidence is not robust to make a definite conclusion about individual differences between antidepressants. Management of sexual dysfunction associated with antidepressants is a complicated clinical problem with several management strategies available. This article reviews the evidence for sexual dysfunction during depression and sexual dysfunction associated with antidepressants. Management strategies of sexual dysfunction associated with antidepressants are also reviewed.

Introduction

At the beginnings of modern-era psychopharmacology, side effects of medications were an unpleasant reality and the evaluation of medications focused mostly on their efficacy. As psychopharmacology has become more refined, the focus on identifying side effects and efforts to minimize them have become more prominent. The supposedly more refined and better-tolerated medications are void of the bothersome side effects of older medications. A good example is the group of selective serotonin reuptake inhibitors (SSRIs). They are not associated with sedation and a host of anticholinergic symptoms. However, the new medications may have their own problems. Examples include the newer antipsychotics associated with a host of metabolic side effects, and, again, the SSRIs. As noted in a meta-analysis by Steffens and colleagues,1 patients taking SSRIs experienced significantly more gastrointestinal problems and sexual dysfunction, whereas treatment with the older tricyclic antidepressants (TCAs) produced significantly more complaints of sedation, dizziness, and anticholinergic symptoms.

Sexual side effects have become one of the more prominent groups of side effects associated with antidepressants. There are several reasons for this relative prominence and the recent increase in interest in these side effects. First, sexual side effects of antidepressants are fairly frequent and probably more frequent with the SSRIs than with the older antidepressants.1 Second, with the refinements of psychopharmacologic agents, more attention is being paid to patient quality of life. Good, unimpaired sexual functioning is considered to be a part of good quality of life. Third, as with other side effects, sexual side effects of antidepressants became an issue in marketing “wars” of antidepressant makers.

Sexual side effects of antidepressants are a clinical reality. As one goal for clinicians in treating depressed patients should be a good quality of life accompanied by unhindered and satisfactory sexual functioning, one may assume that clinicians need to focus, among others, on minimizing the sexual side effects of antidepressants. Although this is certainly true, the situation is more complicated. Sexual dysfunction may have many causes, such as mental illness (especially depression), medical illness, psychosocial factors, medications (psychotropic and non-psychotropic), substances of abuse, and others. This article focuses on sexual dysfunction in depressed patients and during treatment with antidepressants. Possible management approaches are also discussed.

Depression and Human Sexuality

Depression has a profound effect on various body functions. Sexual dysfunction, especially decreased sexual desire, has been frequently reported during depression. For example, Casper and colleagues2 reported that 77% of patients with bipolar depression and 72% of patients with unipolar depression reported loss of libido. Interestingly, the increase in severity of depression was associated with greater loss of libido. However, as pointed out in some recent reviews,3,4 sexual dysfunction associated with depression is not limited to decreased libido. Impaired arousal and orgasm may also occur during depression.5,6 Nevertheless, most experts and clinicians would agree that decreased libido is probably the most frequent sexual dysfunction associated with depression.

There are several caveats regarding the prevalence of sexual dysfunction associated with depression. One is that an exact estimate of prevalence of sexual dysfunction during depression is very difficult and probably impossible to establish at the present time. Sexual dysfunction is reportedly quite prevalent in the general population. In a study by Laumann and colleagues,7 the prevalence of sexual dysfunction in a national probability sample was 43% among women and 31% among men. Interestingly, in a study set in four general practices in England, 41% of women and 34% of men reported having a current sexual problem.8 In another study from Britain,9 53.8% of women and 34.8% of men who had at least one heterosexual partner in the previous year reported at least one sexual problem lasting at least 1 month. These numbers seem fairly consistent, but are they realistic? How do these numbers relate to the estimates of sexual dysfunction associated with depression? Most of the estimates of sexual dysfunction come from epidemiologic studies known for their methodologic problems and overestimates.

The second caveat is that the current definition of sexual dysfunction is unclear and imprecise. Most studies are unclear about the duration of sexual dysfunction, its intensity, possible fluctuation of intensity, course, and other issues. The study mentioned above by Mercer and colleagues9 illustrates how just one of these definitional issues can play havoc in our estimates of sexual dysfunction. As mentioned, the authors reported that 53.8% of women and 34.8% of men had at least one sexual problem lasting at least 1 month. However, persistent sexual problems lasting at least 6 months in the previous year were less prevalent (15.6% of women and 6.2% of men).

The third caveat is that sexual dysfunction in depressed and non-depressed people may have more than one cause. Sexual dysfunction has been reported with many mental (eg, anxiety, substance abuse) and physical disorders (eg, cardiovascular, neurologic, endocrine), which are frequently comorbid with depression. Interpersonal conflicts may also lead to impairment of sexual functioning. In addition, many medications other than antidepressants may cause sexual dysfunction.10 These factors are usually not accounted for in various epidemiologic estimates of sexual dysfunction in the general population or in estimates of sexual dysfunction associated with depression. However, they need to be considered in the clinical situation when addressing sexual dysfunction associated with antidepressants.

Finally, according to a survey in the United Kingdom, 75% of depressed people (versus 70% of the total sample) feel that having a good sex life is fairly or very important (D.S. Baldwin, DM, FRCPsych, as cited in Ferguson11). This observation has an important implication for the treatment of sexual dysfunction associated with antidepressants; good sexual functioning should be one of the treatment goals.

Impairment of sexual functioning clearly occurs as a part of depressive and other mental illness symptomatology. The estimates of its prevalence vary, but may actually be >50%,2,6 probably even 70%.2

Antidepressants and Human Sexuality

Cases of sexual dysfunction associated with TCAs and monoamine oxidase inhibitors (MAOIs) have been reported almost since their introduction.12,13 For various reasons, sexual side effects associated with the older antidepressants were not a prominent clinical issue during the early era of clinical psychopharmacology. Other side effects of these medications were considered more serious, and the quality of certain aspects of life, including sexual function, was not the main focus (if a focus at all) of clinical research. However, as the new, more tolerable antidepressants were developed, interest in sexual dysfunction associated with antidepressants gradually increased. The newer antidepressants started to be used for other indications previously not frequently if ever treated with antidepressants (eg, anxiety disorders), and for less severe conditions (eg, dysthymia). This may have, paradoxically, led to a greater attention to various side effects, including sexual dysfunction.10

The original estimates of sexual dysfunction with some of the new antidepressants were clearly unrealistic. This was probably due to the fact that many of the reports of sexual dysfunction associated with antidepressants were based on spontaneous reporting and not on proactive evaluation of these side effects. For example, the estimate of sexual dysfunction associated with fluoxetine cited in the Physician’s Desk Reference14 volumes during the 1990s was 1.9%. However, various studies demonstrated already during the 1990s that the rates of sexual dysfunction with fluoxetine15,16 and other old and new antidepressants17 are much higher. Newer studies yielded fairly high estimates of sexual dysfunction associated with antidepressants. For example, Montejo and colleagues18 reported the overall incidence of sexual dysfunction with various antidepressants to be 59.1%, with some of them being as high as 72.7% (citalopram) and 70.0% (paroxetine), and some as low as 8.0% (nefazodone) or 3.9% (moclobemide). Bupropion was not evaluated in this study. The antidepressants with the lowest risk of sexual dysfunction in a study by Clayton and colleagues19 were bupropion (22%) and nefazodone (28%), while the SSRIs mirtazapine and venlafaxine were associated with higher rates of sexual dysfunction (36% to 43%). Both of these studies used fairly large population samples but had their share of methodologic problems (eg, lack of baseline evaluation of sexual dysfunction). Nevertheless, the results of these and many other studies suggest that sexual dysfunction is a fairly frequent side effect of antidepressants. Since the early 1990s, hundreds of articles reported the rates of sexual dysfunction associated with antidepressants in various observational, epidemiologic, and comparative studies. A review of all these studies is beyond the scope of this article.

There were also numerous review articles summarizing sexual dysfunction associated with antidepressants.20-30 Most of the authors agree that sexual dysfunction is a relatively frequent side effect of many of the antidepressants in common use today and that the rates of sexual dysfunction are probably higher than those reported by antidepressant manufacturers.26 Some suggest that the likelihood of developing and maintaining sexual dysfunction is determined by the balance of serotonergic, noradrenergic, and dopaminergic properties of individual antidepressants.30

Selective Serotonin Reuptake Inhibitors

The estimates of prevalence of sexual dysfunction associated with antidepressants varies. Most studies suggest that between 30% and 70% of patients treated with SSRIs may experience some form of sexual dysfunction,26,30 most frequently anorgasmia.

Tricyclic Antidepressants

The estimates of sexual dysfunction associated with TCAs vary more, as it reached >90% in some studies (eg, with clomipramine).31 To be fair, it is important to note that this31 was not a study of depressed patients, but rather of patients with obsessive-compulsive disorder. The type or character of sexual dysfunction(s) associated with TCAs seems to vary a bit more, with erectile dysfunction being probably the most frequent, but delayed ejaculation occurring quite frequently with clomipramine, a predominantly serotonergic TCA. Amitriptyline and doxepin may have a lower prevalence of sexual dysfunction than other TCAs.30 However, the rates of sexual dysfunction associated with TCAs (and MAOIs) are more difficult to estimate as these antidepressants have been studied much less with regard to sexual dysfunction. During their heydays, as noted, the focus was on more serious side effects, and there have not been many studies on these drugs lately.

Monoamine Oxidase Inhibitors

Sexual dysfunction associated with MAOIs does not reach >40% in most studies,30 with moclobemide-associated sexual dysfunction occurring least frequently (eg, 3.9%18). Not much is known about the actual prevalence of sexual dysfunction associated with the recently approved transdermal selegiline.

Newer Antidepressants

Some of the newer antidepressants, such as bupropion, reboxetine (not available in the United States), and mirtazapine, seem to be associated with sexual dysfunction substantially less frequently. Nefazodone and trazodone are also rarely associated with sexual dysfunction, though trazodone has been reported infrequently as culprit in cases of priapism.32 Venlafaxine seems to be the agent most frequently associated with sexual dysfunction in the group of newer antidepressants. Finally, duloxetine may have lower rates of sexual dysfunction.33 However, not many studies addressing sexual dysfunction associated with this antidepressant have been published and those published suggest rates between 40% and 50%.34

It is important to note that sexual dysfunction has been reported with all antidepressants used in the treatment of anxiety disorders27 and in healthy volunteers exposed to fluvoxamine (up to 35%35; sexual dysfunction due to antidepressants versus sexual dysfunction due to mood disorder). Antidepressants with possibly lower rates of associated sexual dysfunction are highlighted in Table 1.

Montgomery and colleagues27 carefully examined and critiqued the literature evidence on the existence of sexual dysfunction associated with antidepressants as well as its incidence and prevalence. They concluded that the existing literature confirms sexual dysfunction as a possible side effect of all antidepressants, but it is not sufficiently robust to support claims for differences in the incidence of drug-induced sexual dysfunction between existing antidepressant therapies. They also pointed out several difficulties in the process of determining the rates of antidepressant-induced sexual dysfunction. In addition to the previously discussed difficulties in establishing the “baseline” prevalence of sexual dysfunction in the general population and the greater risk of sexual dysfunction in depression (and anxiety) disorders, these difficulties include the fact that reporting on sexual dysfunction is prone to under-reporting unless careful attention is paid to the method of data collection (spontaneous reporting versus systematic collection); the fact that human sexual behavior is subject to many disparate social and cultural influences, which may vary with time, place, ethnic group, and social class; and that all studies on sexual dysfunction associated with antidepressants had methodologic flaws such as failure to use validated rating scales, failure to include a baseline assessment and/or placebo control group, and lack of randomization and/or blinding.

Management of Sexual Dysfunction Associated with Antidepressants

Management of sexual dysfunction associated with antidepressants begins during the initial evaluation of a patient considered for medication treatment. A good initial evaluation should include a comprehensive sexual history and evaluation of current and premorbid sexual functioning. Gitlin20 and Clayton36 suggest that the evaluation should also include a medical and psychiatric history, identification of substances that may contribute to sexual dysfunction (medications, alcohol, illicit substances), the potential interpersonal context of the sexual dysfunction, endocrine measures if and as indicated (eg, thyroid hormones, testosterone), and a targeted physical examination (including neurologic and genitourinary exam as indicated). As mentioned previously, many studies of sexual dysfunction associated with medications had a major methodologic flaw, which is also a clinical flaw; namely, lack of a baseline evaluation. An experienced clinician is aware of the fact that one cannot always rely on the patient’s memory. Asking the patient 4 weeks later whether he or she had any difficulties with erection or orgasm is not the best way to collect reliable information. The initial evaluation should also include an acknowledgment of the possibility of sexual dysfunction associated with medications and communication of this possibility to the patient.

There may be barriers or obstacles to an appropriate evaluation of sexual functioning. Patients may be hesitant to communicate intimate problems or may have misconceptions about adequate sexual functioning. Thus, questioning about sexual functioning should be sensitive but straightforward and focused. Questions such as “How is your sex life?” are not very helpful. It is better to ask specifically about sexual desire, arousal, and experience of orgasm. Interestingly, physicians themselves may be a barrier to a good evaluation of sexual functioning, as they may feel uncomfortable with the topic or may mistakenly expect patients’ discomfort with this topic. Training in communication skills may help in sexual history taking.37 Physicians of certain specialties (eg, urologists) are more likely to address sexual problems than others (eg, general practitioners).37 Urologists together with psychiatrists and gynecologists are more concerned with sexual history taking compared to other disciplines.38 Clayton36 suggests that a major barrier to appropriate assessment could be the failure to use an adequate and appropriate assessment tool (gender specific, nonintrusive, able to separate illness form medication effects, addressing phase-specific function, brief, able to monitor changes over time, etc). She recommends several instruments such as the Arizona Sexual Experience Scale,39 the Changes in Sexual Functioning Questionnaire–Clinical Version,40 the Derogatis Interview for Sexual Functioning–Short Report,41 and the Rush Sexual Inventory (Table 2).42,43

A good baseline evaluation does not only provide the baseline data, but may also help the treating physician to select an appropriate sexual dysfunction management strategy. A patient who has never been treated with an antidepressant and for whom his or her undisturbed sexual functioning is quite important should probably be started on an antidepressant with a low incidence of sexual dysfunction. On the other hand, a patient who reports a history of sexual dysfunction with a particular antidepressant should probably not be started on that agent.

As with the prevalence and incidence of sexual dysfunction, there have been numerous published case reports, case series, and open studies as well as a few double-blind studies of management strategies. The review of their efficacy and risks is beyond the scope of this article. These studies have been critically summarized in many review articles20-30,44,45 and book chapters.10

The main strategies for antidepressant-induced sexual dysfunction can be found in Table 3. The first strategy is starting treatment with an antidepressant with a low prevalence of associated sexual dysfunction, such as bupropion, mirtazapine, and nefazodone (in some countries also moclobemide or reboxetine, neither available in the US). This strategy could be useful for sexually active, medication-naive patients. A second strategy is waiting for spontaneous remission of sexual dysfunction. This strategy requires a good deal of patience and a good doctor-patient relationship. The effectiveness is usually low. It has been reported that a substantial proportion of patients still report antidepressant-induced sexual dysfunction after several months of treatment with antidepressants.46 This strategy may be useful for patients with a low frequency of sexual activity. A third strategy is scheduling sexual activity around the dose of antidepressant, delaying daily medication intake after the sexual activity. This strategy may work for some of the short half-life antidepressants, but not much is known about its efficacy. A fourth startegy is reduction of dosage. This strategy may be especially useful in patients having other side effects as well.44 However, it may be risky. Patients may relapse if a subtherapeutic dose is reached. A fifth strategy is drug holidays. This strategy involves relatively brief interruption of treatment (eg, 2–3 days) with sexual activity scheduled for the end of this period of interruption. A variant of this approach is the partial drug holiday strategy, ie, lowering the dose of antidepressant for a brief period. This strategy poses several possible risks, such as relapse of depression, discontinuation syndrome in short half-life antidepressants, and encouragement of non-adherence.

A sixth strategy is switching to an antidepressant with a low rate of associated sexual dysfunction, such as bupropion, mirtazapine, and nefazodone (in some countries also moclobemide and reboxetine). This strategy has been described as one of the most effective ones. It should be used especially in relatively treatment-naïve patients (the first or second antidepressant, not the fifth medication that finally helped with depression). The possible risks include relapse of depression and/or emergence of new side effects with the new antidepressant.

A seventh strategy involves use of so-called antidotes or other medications to alleviate sexual dysfunction. The list of antidotes which have been reported includes amantadine, bethanechol, bromocriptine, bupropion, buspirone, cyproheptadine, dextroamphetamine, ephedrine, gingko biloba, granisetron, loratadine, methylphenidate, mirtazapine, nefazodone, neostigmine, pemoline, pramipexole, ropinirole, sildenafil, tadalafil, trazodone, vardenafil, and yohimbine. The usefulness of most of these antidotes has been reported in case reports or case series. As noted previously, according to Osler,47 when too many treatments are offered none is effective all the time and in all cases, and none is curative. The detailed review of efficacy, usefulness, and risk of each antidote is beyond the scope of this article. However, it is important to note that none of these substances has been Food and Drug Administration-approved for the treatment of sexual dysfunction associated with antidepressants.

There may be other adjuvant strategies theoretically helpful in managing antidepressant-associated sexual dysfunction. These include, for example, vacuum pumps and constriction rings. Some suggest behavioral strategies to improve sexual technique25 without clarification of what it really means. Others propose that adding strategies such as cognitive-behavioral therapy, vibrators, lubricants, or suggestion of mutual masturbation may be useful.29 However, the evidence for usefulness of these additional strategies is lacking.

Taylor and colleagues45 critically reviewed the evidence of effectiveness of management strategies for antidepressant-associated sexual dysfunction using the published randomized controlled trials. They found that the only strategies showing statistically significant improvement in sexual dysfunction compared to placebo were the addition of sildenafil, tadalafil, and bupropion (Table 4). (Here the evidence was not unequivocal.) They felt that the addition of sildenafil seems the most promising for erectile dysfunction. They did not find any trials assessing the benefits of psychological interventions, mechanical devices, or changes to antidepressant regimes such as dose reduction or drug holidays. They also pointed out that the currently available evidence is rather limited.

Werneke and colleagues30 suggested, as did many others, that substitution of a possible offending agent by using an alternative antidepressant with less impact on sexual function may be the first-line pharmacologic treatment. They also suggested that the use of antidotes should aim at reversing specific neurotransmitter activities known to mediate sexual dysfunction.

Conclusion

Sexual dysfunction associated with antidepressants remains a complicated clinical problem. It may occur in up to 70% of patients treated with some antidepressants. The estimates of rates of antidepressant-associated sexual dysfunction are complicated by numerous factors such as the occurrence of sexual dysfunction associated with depressive and other disorders, some physical illnesses, medications, and substances of abuse. Studies of sexual dysfunction in general, sexual dysfunction associated with depression, and sexual dysfunction associated with antidepressants have been marred by numerous methodologic issues (unclear definition, lack of baseline assessment, lack of validated assessment tools), which even further complicate the estimation of prevalence of sexual dysfunction associated with antidepressants.

Several management strategies for antidepressant-associated sexual dysfunction have been proposed. However, the evidence for their usefulness is limited. Most experts would recommend as first-line approaches either starting treatment with an antidepressant with a low prevalence of associated sexual dysfunction or switching to this kind of antidepressant if sexual dysfunction with another antidepressant develops. Evidence from literature suggests that adding sildenafil, tadalafil, or bupropion may be useful in some sexual dysfunction associated with antidepressants. The treatment of this side effect should be individualized and still remains a clinical art rather than a science. PP

References

1. Steffens DC, Krishnan KR, Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6(1):10-18.

2. Casper RC, Redmond DE Jr, Katz MM, Schaffer CB, Davis JM, Koslow SH. Somatic symptoms in primary affective disorders. Presence and relationship to the classification of depression. Arch Gen Psychiatry. 1985;42(11):1098-1104.

3. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry. 2006;67(suppl 6):33-37.

4. Williams K, Reynolds MF. Sexual dysfunction in major depression. CNS Spectr. 2006;11(8 suppl 9):19-23.

5. Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord. 1999;56(2-3):201-208.

6. Bonierbale M, Lancon C, Tignol J. The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Curr Med Res Opin. 2003;19(2):114-124.

7. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537-544. Erratum in: JAMA. 1999;281(13):1174.

8. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract. 1998;15(6):519-524.

9. Mercer CH, Fenton KA, Johnson AM, et al. Sexual function problems and help seeking behaviour in Britain: national probability sample survey. BMJ. 2003;327(7412):426-427. Erratum in: BMJ. 2003;327(7416):649.

10. Segraves RT, Balon R. Antidepressants and sexual dysfunction. In: Segraves RT, Balon R. Sexual Pharmacology: Fast Facts. New York, NY: W.W. Norton & Co.; 2003:45-72.

11. Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry. 2001;62(suppl 3):22-34.

12. Greenberg HR. Erectile impotence during the course of tofranil therapy. Am J Psychiatry. 1965;121:1021.

13. Simpson GM, Blair JH, Amuso D. Effects of anti-depressants on genito-urinary function. Dis Nerv Syst. 1965;26(12):787-789.

14. Physician’s Desk Reference. 51st ed. Montvale, NJ: Medical Economic Company; 1997:922.

15. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry. 1992;53(4):119-122.

16. Patterson WM. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry. 1993;54(2):71.

17. Balon R, Yeragani VK, Pohl R, Ramesh C. Sexual dysfunction during antidepressant treatment. J Clin Psychiatry. 1993;54(6):209-212.

18. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(suppl 3):10-21.

19. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.

20. Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry. 1994;55(9):406-413.

21. Harvey KV, Balon R. Clinical implications of antidepressant drug effects on sexual function. Ann Clin Psychiatry. 1995;7(4):189-201.

22. Segraves RT. Antidepressant-induced sexual dysfunction. J Clin Psychiatry. 1998;59(suppl 4):48-54.

23. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry. 2000;61(suppl 11):28-36.

24. Labbate LA. Sexual dysfunction and antidepressants. Primary Psychiatry. 2001;8(4)65-68.

25. Baldwin DS. Depression and sexual dysfunction. Br Med Bull. 2001;57:81-99.

26. Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM. Antidepressant-induced sexual dysfunction. Ann Pharmacother. 2002;36(10):1577-1589.

27. Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced dysfunction. J Affect Disord. 2002;69(1-3):119-140.

28. Baldwin DS. Sexual dysfunction associated with antidepressant drugs. Expert Opin Drug Saf. 2004;3(5):454-470.

29. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163(9):1504-1509.

30. Werneke U, Northey S, Bhugra D. Antidepressants and sexual dysfunction. Acta Psychiatr Scand. 2006;114(6):384-397.

31. Monteiro WO, Noshirvani HF, Marks IM, Lelliott PT. Anorgasmia from clomipramine in obsessive-compulsive disorder. A controlled trial. Br J Psychiatry. 1987;151:107-112.

32. Coccaro EF, Siever LJ. Second generation antidepressants: a comparative review. J Clin Pharmacol. 1985;25(4):241-260.

33. Hirschfeld RM, Vornik LA. Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine. J Clin Psychiatry. 2004;6(suppl 4):46-52.

34. Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol. 2004;14(6):457-470.

35. Nafziger AN, Bertino JS, Goss-Bley AI, Kashuba ADM. Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy. J Clin Psychiatry. 1999;60(3):187-190. Erratum in: J Clin Psychiatry. 1999;60(5):341.

36. Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin Psychiatry. 2001;62(suppl 3):5-9.

37. Tsimtsiou Z, Hatzimouratidis K, Nakopoulou E, Kyrana E, Salpigidis G, Hatzichristou D. Predictors of physicians’ involvement in addressing sexual health issues. J Sex Med. 2006;3(4):583-588.

38. Lewis CE. Sexual practices: are physicians addressing the issues? J Gen Intern Med. 1990;5(suppl 5):S78-S81.

39. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26(1):25-40.

40. Clayton AH, McGarvey El, Clavet GJ. The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull. 1997;33(4):731-745.

41. Derogatis LR. The Derogatis Interview for Sexual Functioning (DISF/DISF-SR): an introductory report. J Sex Marital Ther. 1997;23(4):291-304.

42. Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. Psychopharmacol Bull. 1997;33(4):755-760.

43. Rao D, Zajecka J, Skubiak T. The Modified Rush Sexual Inventory: preliminary psychometric findings. Psychiatry Res. 2005;137(3):175-181.

44. Zajecka J. Strategies for the treatment of antidepressant-related sexual dysfunction. J Clin Psychiatry. 2001;62(suppl 3):35-43.

45. Taylor MJ, Rudkin L, Hawton K. Strategies for managing antidepressant-induced sexual dysfunction: systematic review of randomised controlled trials. J Affect Disord. 2005;88(3):241-254.

46. Montejo-Gonzales AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23(3):176-194.

47. Segraves RT, Balon R. Antidepressants and sexual dysfunction. In: Segraves RT, Balon R. Sexual Pharmacology: Fast Facts. New York, NY: W.W. Norton & Co.; 2003:58.