Drs. Garcia and Lynn are Psychosomatic Medicine/Psycho-Oncology fellows and Dr. Breitbart is Chief of Psychiatry Service, all in the Department of Psychiatry and Behavioral Sciences at Memorial Sloan-Kettering Cancer Center in New York City.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of unapproved/investigational treatments for delirium, depression, fatigue, nausea, pain, and palliative sedation in the cancer population.

Please direct all correspondence to: William Breitbart, MD, FAPM, FAPA, Chief, Psychiatry Service, Vice Chairman, Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, 641 Lexington Ave, 7th floor, New York, NY 10022; Tel: 646-888-0020; E-mail: Breitbaw@mskcc.org.


 

Focus Points

• Antipsychotics play an adjuvant role in the management of pain, nausea, and terminal sedation, but are primary agents in the management of delirium in the palliative care setting.
• Benzodiazepines play an adjuvant role in the management of pain, nausea, and delirium, but are primary agents in the management of palliative sedation.
• Psychostimulants are useful as primary antidepressants in the palliative care setting and are also helpful as adjuvant agents in the management of pain, opioid-induced sedation, and fatigue.
• Antidepressants are effective in the treatment of depression in patients with life-threatening illness, even in the palliative care setting; however, their use near the end of life is limited by the time required for the onset of beneficial effects.
 

Abstract

Psychotropic medications have had significant roles in the management of a variety of symptoms in patients living with chronic medical illness and in patients at the end of life. Intuitively, this may make sense given the considerable overlap of psychological and somatic symptoms in this population. Several reviews of the use of specific agents exist in the literature. However, a brief overview of the most commonly used psychotropic drug classes in palliative care can be helpful for a primary care provider to have as a guide to their usefulness in this population. This article reviews the use of antipsychotics, benzodiazepines, antidepressants, and psychostimulants/wakefulness agents for symptoms such as depressed mood, pain, nausea, palliative sedation, and delirium.

Introduction

Palliative care, as both a movement and a medical subspecialty, has grown over time from a small hospice movement focusing on the care of the actively dying to a clinical specialty focusing on symptom control and provision of support to those living with chronic, life-threatening illnesses in addition to those at the end of their lives.1 Given the burden of disease these patients face, it is perhaps not surprising that psychological symptoms such as depression, anxiety, and hopelessness are as frequent, if not more so, than other target symptoms such as pain.1 Inversely, perhaps in part due to their proximity to mental suffering and its treatment, practitioners of this discipline have long used psychotropic medications for a variety of symptoms, both in traditional and novel ways. However, the evidence upon which some of these practices rest are variable and at times appear more historic than supported by either accumulated clinical experience or empirical evidence. The following is a brief review of some of the ways that psychotropic medications are being used in palliative care and the evidence upon which their use rests.

Antipsychotics

Antipsychotics have played a variety of novel roles in the treatment of the medically ill, including in the palliative care population. These drugs are divided into typical and atypical agents. Typical antipsychotics, which include haloperidol and chlorpromazine, are primarily dopamine (D)2 receptor antagonists, blocking these receptors nonspecifically throughout the brain. This results in both their efficacy against the positive symptoms of psychotic disorders like schizophrenia, but also contributes to the associated negative sequelae such as cognitive and extrapyramidal side effects (EPS). In contrast, atypical antipsychotics are serotonin-dopamine antagonists and specifically block various serotonin and dopamine receptors simultaneously in specific regions of the brain. Through a series of complex interactions between the serotonin and dopamine regulation systems in the various dopamine pathways, atypical antipsychotics help solve the “paradox” initially posed by typical antipsychotics, allowing the treatment of both positive and negative symptoms of schizophrenia while also reducing side effects of generalized dopamine blockade, such as EPS.2

The result is a heterogenous group of drugs with a wide variety of potential actions that have been exploited in novel ways. Their use in the palliative care setting is an example of the flexibility with which these medications are now used, though the evidence for these uses remains variable.

Antipsychotics in Delirium

Delirium is the most common neuropsychiatric disorder reported in the terminally ill.3-10 Various studies report prevalence rates between 20% to 88%,3,5,6,11 with rates rising sharply as the time of death approaches.4,9,10 Although there initially was some concern regarding the reversibility of delirium in the terminally ill, it has been increasingly clear that this is not the case and ~50% of delirium in the terminally ill cancer patients are reversible with appropriate treatment.10 Breitbart and colleagues3 provide a thorough review of the management of delirium in the terminally ill.

Although the mainstay of treatment for delirium still remains identifying and reversing the underlying medical cause, antipsychotics continue to play a role in the symptomatic management of delirium, particularly in the terminally ill where aggressive investigation and intervention must be weighed against comfort and quality of life.5,12-17 A summary of routes of administration and dosages is provided in Table 1.

 

Typical Antipsychotics
Haloperidol has been the traditional drug of choice for the symptomatic treatment of delirium,5 and this remains the case in the palliative care setting.11-14,18 Typically, low doses of 0.5–2.0 mg are administered every 1–8 hours and titrated to effect,5,6,12,14,19 with a maximum daily dose of 20 mg in most patients.3 Lower doses are associated with better tolerability.14 The United States Food and Drug Adminstration has issued a warning about the risk of QTc prolongation with the intravenous (IV) route, requiring routine electrocardiograms in non-terminal patients. Advantages of haloperidol include tolerability (at lower doses), flexibility of route (PO [by mouth], IV, SC [without food], intramuscular [IM]), and relative safety and efficacy.3,5,11,14

Chlorpromazine has been found to be as useful as haloperidol,20 but is considerably more sedating, anticholinergic, and hypotensive.3,14,21 This may make it a reasonable second-line agent for agitation that does not respond to haloperidol. Dosages for chlorpromazine range from 12.5–50.0 mg IV or SC every 4–8 hours, to a maximum of 300 mg per 24 hours for most patients.20,22

Methotrimeprazine is similar to chlorpromazine, and has also been found to be useful in the palliative care setting both as a neuroleptic for delirium and as an anxiolytic and analgesic that is equipotent to morphine.22 Unfortunately, this agent is not available in the US, though it is widely used elsewhere. Dosages for methotrimeprazine range from 10–20 mg IV, IM, or SC every 4–8 hours.20,22,23

There is one case report24 of zuclopenthixol acetate, an injectible typical antipsychotic with a 2–3 day efficacy window, being used successfully in delirium at the end of life. Again, this medication is not available in the US.

Atypical Antipsychotics
Of the atypical antipsychotics, risperidone, olanzapine, and quetiapine have some evidence beyond case reports of efficacy in the management of delirium.3,12,14,25,26 Risperidone has been found to be efficacious at doses of 0.5–2.0 mg PO BID in delirious patients14,27,28; one small double-blind study29 confirmed its efficacy as similar to haloperidol in delirious patients. Further evidence supports that there is reduced risk of EPS with risperidone as compared to haloperidol.30,31

Olanzapine has been found to be efficacious in the treatment of delirium in patients with advanced cancer without the complication of EPS,32 and appears comparable in effect to haloperidol.33,34 However, it may be less useful in those with hypoactive delirium, those with central nervous system (CNS) spread of cancer as the etiology of their delirium, or older patients (>70 years of age).32 Dosing for olanzapine in delirium in the terminally ill appears to be ~2.5–20.0 mg/day PO.14

Quetiapine has a few open-label studies and case reports suggesting efficacy in the treatment of delirium, but sedation was a limiting factor.35,36 Some case reports suggest that ziprasidone and aripiprazole may also be efficacious in delirium,37-39 but the former is limited by its potential cardiac side effects38 and the latter is still very limited in its evidence.39,40

Antipsychotics in Pain

Pain is a common symptom in terminally ill patients, with some suggestion that up to 50% of the terminally ill are in moderate to severe pain,41,42 and that an estimated 25% of cancer patients die in severe pain.41

Although the mainstay of pain management remains opiates, antipsychotics have played an adjunct role, though the evidence for this may be limited.43 Methotrimeprazine, as mentioned previously, is a unique typical antipsychotic that is equianalgesic to morphine, has none of the opiod effects on gastrointestinal motility, and likely also has anti-emetic and anxiolytic effects.41 Fluphenazine has been used successfully in combination with tricyclic antidepressants for neuropathic pain.44

Data for the usefulness of atypical antipsychotics is scanty, but one small prospective study45 showed improvement of pain scale scores, reduced need to increase opiates daily, and some mild sedative effects with the adjunct use of olanzapine with opiates in cancer pain.

Antipsychotics in Nausea and Emesis

Nausea is a very common experience in both the active and palliative phases of treatment of cancer.46-48 Although the bulk of the literature reflects treatment of nausea and emesis in patients outside of the palliative setting, a few studies do suggest that the same antipsychotics found to be useful during chemotherapy may be useful in the hospice setting.46-50

Phenothiazines, including chlorpromazine, methotrimeprazine, and perphenazine, have been found to be useful as anti-emetics via D2 blockade.49 Prochlorperazine belongs to this family of antipsychotics, though its primary role has always been as an anti-emetic.49 Haloperidol and droperidol have also been found to be useful for emesis via case reports and small trials,51-53 including in the palliative population.46,47

Aside from prochloperazine, olanzapine has perhaps the most robust evidence for its anti-emetic effect in cancer patients both in the acute and palliative treatment phase.48,49 It is useful both for the acute and delayed emesis of chemotherapy54,55 as well as for intractable nausea in palliative care patients.48,50 A proposed mechanism of action is its strong antagonism of serotonin (5-HT)6 and 5-HT3, which along with its selective D2 receptor antagonism may work at several places in the central regulation of emesis.56

Antipsychotics in Palliative Sedation

Palliative sedation, or terminal sedation, is a controversial practice with many definitions. Perhaps the most inclusive and general is “the use of pharmacological agents to induce unconsciousness for treatment of truly distressing and refractory symptoms in the terminally ill.”57

Although there are no official clinical guidelines in the US, practitioners are guided by those of other nations58 as well as some limited data.59 There is little role for antipsychotics in palliative sedation except in the context of treating delirium. However, chlorpromazine has been used based on clinical experience, in part due to its sedating effects and relatively easy titration.57 Its dosing and titration appears to be very similar to its use in delirium.

Benzodiazepines

Benzodiazepines represent a class of anxiolytics that bind selectively to gamma-aminobutyric acid receptors, resulting in several therapeutic effects (sedation, anxiolysis, muscle relaxant, anticonvulsant) and side effects (amnestic agents, ataxia, tolerance, and withdrawal).2 Like antipsychotics, these agents have played a wide variety of roles in palliative care throughout the decades, sometimes despite limited evidence.60,61

Benzodiazepines in Delirium

Although historically benzodiazepines played a significant role in the treatment of delirium, there has been sufficient accumulated evidence to clarify that they are not useful as single agents in this disorder, both in non-palliative and palliative populations, and likely worsen clinical outcomes when used alone.5,14,17,19 This appears to be largely due to their cognitive and disinhibitory effects.14 In contrast, there is some evidence that lorazepam may have a role as adjunct therapy for hyperactive deliriums that do not respond to haloperidol alone.14 This relatively rapid-acting and short-lived agent may be more effective in rapidly sedating agitated patients than haloperidol alone, and may also help minimize the EPS associated with haloperidol.62 A typical dosing for this would be 1–2 mg PO/IV/IM Q1–4 hours, to be given in conjunction with regularly scheduled haloperidol.14

Benzodiazepines in Pain

As in delirium, benzodiazepines have had a historic role in the treatment of both acute and chronic pain, but accumulating evidence suggests that their role is likely to be adjunct at best, perhaps more related to their anxiolytic effect.63 There is some suggestion in the literature that their anti-convulsant properties may provide some efficacy in neuropathic pain.64 One study65 in particular noted that alprazolam appeared to be useful as adjunct treatment for phantom limb pain in cancer patients. Similarly, clonazepam may be useful in the management of certain types of neuropathic pain in cancer patients.66,67 Interestingly, an earlier study63 examining the possible role of alprazolam in increasing the potency of morphine found little improvement of analgesic effect but a significant improvement in opiate-related nausea.

Benzodiazepines in Nausea and Emesis

Benzodiazepines appear to have valuable adjunct roles in nausea and emesis, largely in the treatment of anxiety and anticipatory nausea and emesis associated with chemotherapy, particularly in children.49,68-70 One study71 found the adjunct efficacy of lorazepam added to metoclopromide or dexamethasone regimens for chemotherapy-induced nausea to be equivalent to the adjunct efficacy of diphenhydramine added to these same regimens, but with better control of anticipatory anxiety symptoms and superior patient satisfaction in the lorazepam arm of treatment. Another study72—a randomized, double-blind, crossover design—showed improved efficacy of lorazepam over placebo when added as an adjunct to prochlorperazine for chemotherapy-induced nausea. However, there was no evidence found in the literature in this review to support the role of benzodiazepines as single or primary anti-emetics.49 No clear guidelines for dosing of benzodiazepines for the treatment of emesis were found.

Benzodiazepines in Palliative Sedation

Palliative sedation is one of the few areas of palliative care where benzodiazepines are considered a mainstay of treatment.57-59,73 Although historically, opiates and occasionally antipsychotics were utilized for this purpose, existing palliative sedation guidelines recommend midazolam as the preferred agent for this intervention.57 The reasoning for this, supported by primarily accumulated clinical experience, is that deliberate overdose of opiates to the point of sedation often result in other unpleasant side effects, such as delirium, restlessness, sweating, myoclonus, and nausea.57-59 Suggested dosing for midazolam in palliative sedation is 0.4 mg/hour, with dose escalation to 4.5–10.0 mg/hour.57

Antidepressants

Similar to other psychotropic medications, antidepressants as a class can be used for the treatment of several different symptom profiles in the terminally ill. All antidepressants act through the monoamine transmitter system—impacting the release, breakdown, or reuptake of serotonin, norepinephrine or both—ultimately in delayed effect, impacting gene expression in the neurons targeted by those monoamines.2 (Table 2 lists medications by class and clinical doses.74)

 

 

 

As a class, through these similar mechanisms, these drugs can all cause to different extents neuropsychiatric side effects. Serotonin syndrome is an uncommon but potentially life-threatening toxicity from excessive serotonergic activity which clinically presents as rapid onset tremor, hyperreflexia, mental status changes, and autonomic instability. Definitive treatment is the removal of the serotonergic agent. Due to the potential serotonergic reuptake inhibition of some opiate analgesics (including fentanyl), care should be taken.75 These agents are also associated with akathisia—the subjective feeling of restlessness and objective motor agitation—usually in the lower limbs, bilaterally, and symmetrically.75 This is similarly treated by removal of the causative agent.

Depression

Estimates of depression in the palliative care setting vary widely, depending on the diagnostic methods used.76,77 Some have cited rates from 13% to 26% in the terminally ill.78 Depression is thought to reduce quality of life and be associated with a desire for hastened death.78-82 Yet, treatment of depression is complicated by the fact that most traditional antidepressants take several weeks to have therapeutic effect; the goal of intervention in this setting is rapid onset of action. Thus, considerations for antidepressants are often based largely on side effect profiles, potential drug-drug interactions, and treatment goals in the setting of life expectancy.78

Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are generally considered the first line for the treatment of depressive disorders in the medically ill due to the high efficacy and low side effect profile of this class. However, these medications take several weeks to show therapeutic effect. In patients with a life expectancy of several months, these medications have been shown to be helpful and effective.83,84 Older SSRIs, fluoxetine and paroxetine, are potential inhibitors of cytochrome P450 enzymes, increasing the potential for drug-drug interactions.64 Sertraline, citalopram, or escitalopram carry a lower risk of inhibition and thus potential drug interactions.64

Tricyclic Antidepressants
While tricyclic antidepressants (TCAs) have been shown to be effective, with sufficient time to therapeutic benefit,84 they are less frequently used for depression alone given their anticholinergic, anti-andrenergic, and antihistaminic side effects. TCAs are more likely to be chosen for combined treatment of depression and neuropathic pain.

Serotonin Norepinephrine Reuptake Inhibitors
Serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine are generally found to be well tolerated and with side effect profiles similar to SSRIs. Venlafaxine acts as an SSRI at lower doses, usually only inhibiting norepinephrine at doses >150–225 mg. Both are noted to contribute to hypertension.

Other Antidepressants
Buproprion, acting through reuptake inhibition of dopamine and some norepinephrine, is a well-tolerated antidepressant, noted to have some mild stimulating effects providing benefit to the depressed patient with prominent fatigue. It is noted to lower seizure threshold and thus is to be used with caution in patients with CNS tumors, pathology, or underlying seizure disorders. Mirtazepine, a noradrenergic and specific serotonin antidepressant, has delayed antidepressant effects through its actions at 5-HT2 and 5-HT3, but also causes rapid weight gain and sedation through its high affinity for H1; these side effects can be beneficial for patients with insomnia and weight loss.85

Pain

One of the most difficult problems in palliative care is achievement of appropriate and sufficient palliation from pain. Many antidepressants have been shown to have analgesic effects both directly and through augmentation of opioid analgesics, independent of depressive symptoms.86 Most studies investigate the impact of these medications in addition to opioid compounds rather than as an alternative.

Tricyclic Antidepressants
TCAs have the most robust evidence for efficacy in the treatment of pain, likely three routes: antidepressant activity, potentiation of analgesic activity,87,88 and direct analgesic effects.89 Amitriptyline is the most widely studied in many different types of pain, yet efficacy has been shown for imipramine, desipramine, nortriptyline, clomipramine, and doxepin.64,87,89-91 Evidence suggests that dosing for pain control should be targeted to serum levels similar to those sought for antidepressant effect.91

Selective Serotonin Reuptake Inhibitors
Some trials have demonstrated efficacy of the SSRIs in the treatment of neuropathic and cancer-related pain intensity, usually equal to or approaching that of the TCAs. Fluoxetine has been demonstrated to decrease cancer-related pain intensity84 and to act as a potentiator of morphine.92 Similarly, paroxetine and citalopram have demonstrated efficacy in the treatment of neuropathic pain, in some cases equal to that of imipramine.93,94 Similar evidence has yet to be specifically demonstrated for the newest of the SSRIs.

Fatigue

Fatigue is found to be a highly distressing and prevalent symptom which impacts patients’ quality of life.95 Fatigue is described as a sense of tiredness or exhaustion out of proportion to recent activity and is not responsive to rest.96 It can be found as a side effect of opiate treatment (sedation) or associated as a symptom of depression. However, it is increasingly acknowledged as an independent complaint.97

Buproprion
Bupropion is often considered to be a “stimulant-like” antidepressant. It has been shown in open-label trials of the sustained release formulation, at doses between 100–300 mg, to demonstrate significant improvement in the treatment of fatigue in both depressed and non-depressed cancer patients.98,99

Selective Serotonin Reuptake Inhibitors
Several clinical trials of SSRIs for the treatment of fatigue have failed to show any significant effect of this drug class on fatigue alone.100-102 Thus, SSRIs are thought only to have a role in the treatment of fatigue as a symptom of a greater depressive disorder.

Psychostimulants and Wakefulness-promoting Agents

Traditional psychostimulant medications, methylphenidate and dextroamphetamine, act predominately through release of dopamine from the presynaptic terminal, and additionally through blocking reuptake of that same dopamine.2 These medications are generally considered to be well tolerated but do have known side effects, including agitation, insomnia, tachycardia, hypertension, and—as a result of the increased dopamine levels—psychotic symptoms.2,103 In addition to tablet forms, methylphenidate is available in a transdermal patch.

Modafinil is a novel psychotrophic agent used to promote wakefulness in settings of excessive sleepiness; it is used for narcolepsy, obstructive sleep apnea, and shift work. While it may block some dopamine reuptake similar to the stimulants, it is thought to enhance the activity of the hypothalamic wakefulness center, promoting release of histamine, orexin, and hypocetin.2,95 It is has less potential for dependence and fewer side effects than traditional stimulants.

Depression

Methylphenidate and dextroamphetamine have been shown in the palliative care population to be a rapid and effective treatment of depressive symptoms.104-107 Response is anticipated within 48 hours of initiation of treatment with psychostimulants.108 While attention must be paid to possible side effects (agitation, insomnia, tachycardia, hypertension, or rarely psychotic symptoms), these medications are noted to be very well tolerated in this population.103

Pain

Psychostimulants have been shown to have clear and rapid onset effects on pain. In addition to treating the excessive sedation associated with opiate treatment, both methylphenidate and dextroamphetamine have been shown in small clinical trials to potentiate the therapeutic effects of opiates.109-112

Fatigue

Methylphenidate has been demonstrated in both clinical trial and open-label studies to show significant improvement in the treatment of fatigue.95,109-111 Dosing of methylphenidate has ranged from 5 mg/day–10 mg BID and as high as 30 mg total daily dose.95,109-111,113,114 While some studies have reported patients to be largely free of troublesome side effects, others noted patients experiencing problems with insomnia and cardiovascular toxicity.

Used at low doses (200–225 mg) in chronically ill and cancer patients, modafinil has been demonstrated in open-label trials to show significant reduction in fatigue following several weeks of treatment without significant side effects.95,115 Clinical experience suggests that this effect can be achieved quite rapidly and does not require weeks of treatment for improvement. However, randomized clinical trials are still needed to confirm these clinical observations.

Conclusion

Psychotropic medications have had significant roles in the management of a variety of symptoms in patients living with chronic medical illness and in patients at the end of life. This article provides a summary of the available evidence for the traditional and novel indications for antipsychotics, benzodiazepines, antidepressants, and psychostimulants. PP

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51.    Plotkin DA, Plotkin D, Okun R. Haloperidol in the treatment of nausea and vomiting due to cytotoxic drug administration. Curr Ther Res Clin Exp. 1973;15(9):599-602.
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54.    Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer. 2005;13(7):529-534.
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63.    Coda BA, Mackie A, Hill HF. Influence of alprazolam on opioid analgesia and side effects during steady-state morphine infusions. Pain. 1992;50(3):309-316.
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79. Block SD. Assessing and managing depression in the terminally ill patient. ACP-ASIM end-of-life care consensus panel. American College of Physicians – American Society of Internal Medicine. Ann Intern Med. 2000;132(3):209-218.
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92. Hynes MD, Lochner MA, Bemis KG, Hymson DL. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors. Life Sci. 1985;36(24):2317-2323.
93. Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42(2):135-144.
94. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992;52(5):547-552.
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Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge

Anita H. Clayton, MD

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Primary Psychiatry. 2003;10(1):55-61

 

Dr. Clayton is professor and vice chairin theDepartment of Psychiatric Medicine at the University of Virginia Health Systems in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer. No financial, academic, or other support was received for this work.

Please direct all correspondence to: Anita H. Clayton, MD, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22908-0623; Tel: 434-924-2241; Fax:?434-924-5149; E-mail: ahc8v@virginia.edu


 

Abstract

How can the occurrence of antidepressant-associated sexual dysfunction be minimized? In prospective studies, sexual dysfunction has been reported by up to 70% of patients using serotonergic antidepressants, which are associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or minimally affect serotonergic neurotransmission. Three approaches to managing antidepressant-associated sexual dysfunction include reduction or elimination of antidepressant doses suspected of causing sexual dysfunction, use of a second medication to reverse sexual dysfunction, or substitution of a second antidepressant not associated with sexual side effects. The introduction of new antidepressants augments the options for controlling or avoiding sexual dysfunction. For symptoms of depression, the norepinephrine and dopamine reuptake inhibitor bupropion sustained-release and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective as serotonergic antidepressants, but with a much lower incidence of sexual dyfunction.

Introduction

Clinically depressed individuals often suffer from sexual dysfunction, which can arise from numerous causes, including the depression itself, comorbid psychiatric or medical disorders, antidepressant therapy, and concomitant medications.1 A primary role of antidepressant therapy in the etiology of sexual dysfunction has become increasingly recognized since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.2 While SSRIs and other medications that enhance serotonergic function are most strongly associated with orgasm dysfunction,3-6 they may also be associated with disorders of other phases of the sexual response cycle, including desire and arousal.7-9 As data from well-controlled studies on the sexual side effects of SSRIs and other serotonergic antidepressants have accumulated over the last decade and a half, health care providers’ concern about these side effects and interest in exploring treatment strategies that minimize or eliminate sexual side effects have grown. This review, based on MEDLINE searches and systematic review of congress abstracts, considers clinical aspects, prevalence, and possible mechanisms of antidepressant-associated sexual dysfunction with a discussion of strategies to minimize the occurrence of this side effect.

Antidepressant-Associated Sexual Dysfunction

Clinical Consequences

Sexual dysfunction can adversely affect quality of life, self-esteem, and interpersonal relationships. These effects are of particular concern among patients with depression, in whom these issues may already be compromised. Moreover, antidepressant-associated sexual dysfunction may lead to medication noncompliance and premature discontinuation and thereby may increase the risk of relapse or recurrence of depression.10,11

In an open-label study of 1,022 patients with a mean 40 years of age, 59.1% reported antidepressant-associated sexual dysfunction.10 The study analyzed the following antidepressants: citalopram, paroxetine, venlafaxine, sertraline, fluvoxamine, fluoxetine, mirtazapine, nefazodone, amineptine, moclobemide, clomipramine, imipramine, maprotiline, phenelzine, and trazodone. Of those with sexual dysfunction attributed to antidepressants, 38.3% rated themselves as being concerned enough about sexual dysfunction to discontinue antidepressant therapy (Figure 1). Another 34.5% indicated that, although they did not intend to discontinue antidepressant therapy because of it, they and/or their partner were concerned or distressed about sexual dysfunction. That nearly 4 of 10 patients in this study were concerned enough about their sexual dysfunction to discontinue their antidepressant is worrisome in view of the fact that noncompliance with the therapeutic regimen may result in relapse or recurrence of depression.

In a patient survey (N=350) reported in 2001, 60% of patients indicated that they had stopped taking their prescribed antidepressant at one time or another, and 22% of patients indicated that they did not always take their antidepressant medication exactly as prescribed.11 Sexual dysfunction was one of the top five reasons for stopping medication or failing to use medication as prescribed. When asked to rate the impact of specific side effects, one fourth of the patients indicated that it would be extremely difficult to live with the side effects of orgasm dysfunction or erectile dysfunction.

Assessment

Across studies in which sexual dysfunction is a prospectively defined endpoint, the condition has been reported in up to 70% of patients using antidepressants such as SSRIs.9,12 Lower frequencies of sexual dysfunction are reported in studies in which sexual function was not objectively assessed or patients were not specifically queried.3,9 Variance in estimates of the prevalence of sexual dysfunction arises primarily from the fact that some studies specifically queried patients regarding sexual dysfunction whereas other studies relied on patients’ spontaneous reports. Because patients are usually reticent to initiate discussion about sexual dysfunction with their health care provider, reliance on spontaneous report of sexual dysfunction underestimates the commonality of the condition. This fact is illustrated by the results of a study (N=344) that assessed sexual dysfunction both via patients’ spontaneous reports and with a questionnaire. Whereas only 14% (28 of 200) of patients spontaneously reported sexual dysfunction, 58% (200 of 344 patients) subsequently reported sexual dysfunction when specifically asked.13

From a practical perspective, these results emphasize the importance of having health care providers discuss sexual function with their patients both before antidepressant therapy is initiated (to obtain a baseline measure) and during antidepressant therapy. Normalizing the issue by opening with an explanation of the frequency of sexual disorders in the general population and among depressed patients, as well as the frequency of sexual disorders associated with specific treatments for depression, can help remove the barriers to discussing sexual functioning with patients.1

Using the medical model to evaluate each stage of the sexual response cycle (desire, arousal, orgasm, resolution) or employing an assessment tool such as the Arizona Sexual Experiences (ASEX) Scale14 or the Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C)15 is also important in identifying and assessing sexual dysfunction. Once the presence of sexual dysfunction is confirmed, further evaluation is necessary to differentiate antidepressant-associated sexual dysfunction from sexual dysfunction that may be attributed to other causes.1 This evaluation should compare a sexual history with the current level of sexual functioning and should eliminate other contributing factors including comorbid medical or psychiatric conditions, medications, or substances of abuse. Because both erectile dysfunction and decreased libido commonly occur as symptoms of depression, it is important to determine the patient’s level of sexual functioning prior to the onset of depression to determine the relative contributions of depression and antidepressant therapy.1

Besides reliance on spontaneous reports, other factors that explain variability in estimates of the prevalence of sexual dysfunction include misattribution of depression-associated sexual dysfunction to antidepressant use, failure to account for other established correlates of decreased sexual function such as advancing age and physical illness, and variation among studies in the definition and measurement of sexual dysfunction. Moreover, many studies reporting on sexual dysfunction did not prospectively define it as an endpoint and were often not sufficiently powered to assess the influence of specific variables or interventions.

Several recent studies that have controlled for these methodological problems provide useful data on the prevalence of antidepressant-associated sexual dysfunction.4-6,16-18 The data from these recent studies are consistent in showing that the prevalence of sexual dysfunction differs by physiologic mechanism of the antidepressant: antidepressants affecting serotonergic neurotransmission are reliably associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or only minimally affect serotonergic neurotransmission. For example, in the first study to employ a validated rating scale to assess the effects of the 10 new-generation antidepressants on sexual dysfunction in a large population of patients, 37% of 6,297 patients consulting 1,100 primary care physicians in the United States, reported sexual problems associated with antidepressant use.18 The lowest rates of sexual dysfunction across all antidepressant groups were in patients treated with bupropion (22% and 25%, for the immediate-release and sustained-release [SR] forms, respectively) and nefazodone (28%). Patients treated with bupropion SR or nefazodone had a statistically significantly lower prevalence rate of sexual dysfunction than patients taking SSRIs (citalopram, fluoxetine, paroxetine, sertraline), or venlafaxine extended-release. The mean prevalence rate of presumed antidepressant-associated sexual dysfunction was 24.4% among a prospectively defined subpopulation of patients free from other probable causes of sexual dysfunction (ie, patients were 18–40 years of age, had no history of sexual side effects on previous antidepressants, had used their current antidepressant for at least 3 months, were not taking concomitant medications affecting sexual functioning, had no comorbid illness that would affect sexual functioning, and had a history of at least some sexual enjoyment). Patients treated with bupropion SR had the lowest prevalence (6.7%) of sexual dysfunction (Table 1).

Manifestations

The four phases of the sexual response cycle are desire, arousal (erection in men, engorgement and lubrication in women), orgasm, and resolution. The aspect of sexual functioning most often affected by serotonergic antidepressants is the ability to achieve orgasm, which is either delayed or does not occur in many patients treated with antidepressants.7 Because orgasm dysfunction, unlike other sexual problems such as decreased libido, rarely occurs as a manifestation of depression per se, it is more easily attributed to pharmacotherapy than are sexual symptoms that frequently occur as manifestations of depression.3 In addition to orgasm dysfunction, the serotonergic antidepressants have been linked to erectile dysfunction and decreased libido, although the data associating these sexual side effects with antidepressant therapy are less consistent.7

Mechanisms of Action

The mechanism of antidepressant-associated sexual dysfunction has not been determined. The range of possible mechanisms includes (1) nonspecific neurologic effects (eg, sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.8 It is probable that antidepressants impact several of these physiologic substrates of sexual function.

The association of some antidepressants and of depression itself with sexual dysfunction is not surprising in view of the fact that many of the neurotransmitter systems implicated in depression, including the serotonin, dopamine, and norepinephrine systems, are also implicated in control of sexual function. Animal research and data from studies in human subjects suggest that sexual behavior and function are enhanced by increases in brain dopaminergic function and inhibited by increases in brain serotonergic function.2,8,19,20 The latter observation is consistent with the association of serotonergic antidepressants with sexual dysfunction.

Management Strategies for Antidepressant-Associated Sexual Dysfunction

Four general approaches to managing antidepressant-associated sexual dysfunction have been adopted (Table 2). The first approach is deciding not to intervene for antidepressant-associated sexual dysfunction in the hope that spontaneous remission will occur. The second approach is to reduce or eliminate doses of the antidepressant suspected of causing sexual dysfunction. The third approach involves use of a second medication as an antidote to reverse sexual dysfunction. Finally, the fourth approach involves substitution of a second antidepressant unlikely to cause sexual side effects. Each of these strategies for managing antidepressant-associated sexual dysfunction is reviewed below.

No Intervention

Some health care providers decide not to intervene in the case of antidepressant-associated sexual dysfunction in the hope that sexual side effects may spontaneously remit over time.4 Spontaneous remission of antidepressant-associated sexual dysfunction has been reported in case studies.21,22 However, recent research suggests that it infrequently occurs within the first 6 months of initiation of therapy. In a prospective, open-label study of 1,022 outpatients taking antidepressants, 59% reported antidepressant-associated sexual dysfunction.10

Of the patients reporting sexual dysfunction, only 9.7% of them reported total improvement or spontaneous remission at the end of 6 months of antidepressant therapy; 79% of them reported no improvement. These data, suggesting that antidepressant-associated sexual dysfunction does not promptly remit, are consistent with data from the 16-week controlled comparison of sertraline and bupropion SR.16 In that study, sertraline-associated sexual dysfunction was observed at the end of the first treatment week (the initial assessment following the start of treatment) and was maintained throughout the 16-week treatment period. If spontaneous remission does not occur, failure to intervene may increase the likelihood of noncompliance with the antidepressant regimen—particularly among patients to whom sexual dysfunction is a significant concern.

Reducing or Eliminating Antidepressant Doses

Reducing the dose of antidepressant medication has been tried in attempts to ameliorate antidepressant-associated sexual dysfunction.8 This strategy has not been systematically assessed in controlled clinical studies but has been reported effective with an SSRI and a monoamine oxidase inhibitor.23,24 Depressive symptoms may reemerge with dose reduction.

Antidepressant drug holidays have also been employed as a strategy for reducing antidepressant-associated sexual dysfunction. Like the dose-reduction strategy, the efficacy of drug holidays in reducing antidepressant-associated sexual dysfunction has not been systematically studied. Positive results were obtained in one open-label, 30-patient study in which patients discontinued sertraline or paroxetine, but not fluoxetine, for the weekend. Discontinuation was associated with significant improvement in sexual functioning without a worsening of depressive symptoms.25

As drug holidays may result in antidepressant discontinuation syndrome and may provide a risk for relapse of depression, they are not an ideal strategy for most patients. Drug holidays may also limit patients’ spontaneity with respect to the timing of sexual activity. Furthermore, advising drug holidays for improvement of sexual dysfunction may encourage patients to be noncompliant with the treatment regimen during times when drug holidays are not advised or appropriate. Finally, in cases in which a drug holiday is effective in reducing sexual side effects, reinstatement of antidepressant therapy is likely to result in the reemergence of sexual dysfunction.

Reemergence of sexual dysfunction due to antidepressants was evaluated in a double-blind rechallenge study enrolling depressed patients who reported impairment in sexual function upon initiation of therapy with sertraline 100 mg OD.26 Patients discontinued sertraline for a 2-week period, and if their sexual functioning normalized during the 2-week period, were assigned to 8 weeks of double-blind treatment with sertraline 50 mg OD or the mixed serotonin antagonist/reuptake inhibitor nefazodone 100 mg BID. Beginning with the first week of reinstatement of sertraline therapy, sexual dysfunction reemerged. Whereas approximately 15% of patients were dissatisfied with sexual function before reinstatement of sertraline therapy, 50% were dissatisfied at week 1 of sertraline reinstatement. When doses were increased to 100 mg/day sertraline and 150 mg nefazodone BID during the second week of therapy, the proportion of sertraline-treated patients dissatisfied with sexual function increased to approximately 80%, which was consistently maintained through the remainder of the 8-week treatment period. These data suggest that drug holidays are not a viable long-term strategy for controlling antidepressant-associated sexual side effects, particularly for a chronic disease such as depression, which often requires life-long pharmacotherapy.

Adding an Antidote

Daily administration of pharmacotherapies that reverse sexual dysfunction and administration of antidotes acutely before sexual activity have also been tried. Agents used for this application are listed in Table 3.27-52 Although addition of an antidote can be successful in reducing the incidence of sexual side effects, it entails polytherapy, which relative to monotherapy increases the overall risk of side effects and drug interactions.

Of all of the agents administered as antidotes, only bupropion SR and buspirone have been demonstrated effective in placebo-controlled trials as well as open-label studies involving both sexes.27,32-37,51 Unlike some of the other augmentation therapies that have been tried, both bupropion SR and buspirone added to SSRI regimens appear to be well-tolerated. None of the other possible antidotes to antidepressant-associated sexual dysfunction have been evaluated in placebo-controlled studies. Evidence for their use is derived primarily from case reports and small, open-label investigations as follows:

• Several authors have reported that amantadine used for at least 2 days before sexual activity or on a regular basis reverses SSRI-associated sexual dysfunction.28-31 In a retrospective chart-review study involving records from 594 patients, amantadine was less effective than yohimbine at reversing SSRI-associated sexual dysfunction.52

• Sildenafil, which is currently approved only for management of erectile dysfunction in men, was reported in an open-label investigation to work as an antidote to antidepressant-induced sexual dysfunction in both men and women.38 Sildenafil is one of the only antidotes that can be taken on an as-needed basis shortly prior to sexual activity.

• Psychostimulants used intermittently or on a daily basis have been reported to be effective at reversing SSRI-associated sexual dysfunction.27,49 Possible drawbacks
of the use of psychostimulants include impairment of sexual function with increasing dose, the potential for abuse, and cardiovascular side effects.

• Ginkgo biloba has been reported in case reports and one uncontrolled study to counter SSRI-induced sexual dysfunction.27,46 As it is an over-the-counter herbal extract, its safety profile has not been assessed with the rigor that is applied to prescription medicines.

• Serotonin (5-HT)2 antagonists such as nefazodone and mirtazapine, as well as the 5-HT2 antagonist and antihistamine cyproheptadine, have been reported to be effective antidotes to antidepressant-associated sexual dysfunction.42-45,47,48 Cyproheptadine administered as daily therapy can interfere with the antidepressant efficacy of SSRIs.42,53 Administered acutely or chronically, it may also cause sedation, which can interfere with sexual function.

Substitution With an Antidepressant Unlikely to Cause Sexual Dysfunction

The development of new antidepressants with little or no adverse effects on sexual function has provided new opportunities for managing antidepressant-associated sexual dysfunction. Health care providers increasingly manage antidepressant-associated sexual dysfunction by starting new patients on an antidepressant shown to cause less sexual dysfunction than the SSRIs and venlafaxine. Similarly, in patients with antidepressant-associated sexual dysfunction, the sexually impairing antidepressant may be replaced with an antidepressant not associated with negative sexual side effects. These strategies have been shown to be effective with the nonserotonergic antidepressant bupropion SR as well as with the mixed serotonin antagonist/reuptake inhibitor nefazodone.7

Feiger and colleagues17 conducted a randomized, double-blind, parallel-group study to compare 6 weeks of treatment with nefazodone (n=71; mean modal end-of-treatment dose of 456 mg/day) and sertraline (n=72; mean modal end-of-treatment dose of 148 mg/day) with respect to efficacy, tolerability, and effects on sexual function. Sexual function was evaluated weekly via questionnaire. The results show that sertraline, but not nefazodone, significantly impaired sexual function, particularly among men. The following was noted among men during the last treatment week:

(1) 100% of those receiving nefazodone reported that they “fully enjoyed” or “sometimes enjoyed” sex compared with 57% of those receiving sertraline;

(2) 89% of those receiving nefazodone were at least moderately satisfied with sex compared with 50% of men receiving sertraline (Figure 2);

(3) 19% of those receiving nefazodone compared with 67% of those receiving sertraline reported difficulty with ejaculation; and

(4) 18% of those receiving nefazodone compared with 67% of those receiving sertraline indicated that they frequently, usually, or always took a long time to ejaculate.

Among women, 74% of those receiving nefazodone compared with 59% of those receiving sertraline were at least moderately satisfied with sex (Figure 2). Nefazodone-treated women achieved orgasm more easily and were more satisfied with the ability to achieve orgasm than were sertraline-treated women.

The effects on sexual function of bupropion SR have also been assessed in double-blind, head-to-head comparisons with SSRIs in patients with depression.4-6,16 In the first study, patients with moderate or severe depression received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks.16 To be included in the study, patients had to have normal sexual function (defined as absence of sexual arousal disorder, orgasm dysfunction, premature ejaculation, dyspareunia, or vaginismus) at baseline prior to the initiation of treatment, although sexual desire disorder associated with the depression could be present. The results demonstrate that the cumulative incidence of orgasm delay or failure was significantly (P<.001) greater among sertraline-treated patients (52%) than among bupropion SR-treated patients (8%), as was the overall incidence of sexual desire disorder (34% of sertraline-treated patients, 21% of bupropion-treated patients; P<.05) and the cumulative incidence of sexual arousal disorder (16% of sertraline-treated patients, 4% of bupropion SR-treated patients; P<.05). Consistent with these data, the percentage of patients satisfied with their sexual function at the end of the study increased substantially for bupropion SR (57% to 79%) but did not change for sertraline (57% to 58%). While bupropion SR had a better sexual tolerability profile than did sertraline, it conferred comparable efficacy for depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Severity, and the Clinical Global Impressions Scale for Improvement.54

These data were substantiated by two double-blind, placebo-controlled, 8-week studies that replicated the findings of the first study.4,5 The placebo-controlled studies also extended the earlier findings by demonstrating that the effects of bupropion SR on the incidence of orgasm dysfunction, sexual desire disorder, and sexual arousal disorder did not differ from those of placebo (with the exception of sexual arousal disorder on day 56 of treatment in one study4) in patients with major depression. In both of these studies as in the first one, differences between bupropion SR and sertraline were most marked for orgasm delay or failure, which of the sexual problems assessed was the most common one reported with sertraline therapy (Figure 3).

In a similar placebo-controlled study prospectively designed to compare the effects of bupropion SR (100–400 mg/day) with those of fluoxetine (10–60 mg/day) on sexual dysfunction, significantly more fluoxetine-treated patients experienced orgasm dysfunction beginning by the second treatment week and continuing throughout the study compared with bupropion SR- or placebo-treated patients (P<.001, Figure 4).6 This effect was observed both in patients defined as clinical responders (ie, those with a 50% decrease in total HAM-D scores during treatment) and in patients experiencing remission (ie, those with total HAM-D scores improved to less than 8). Worsened sexual functioning, decreased sexual desire, sexual arousal disorder, and dissatisfaction with sexual functioning were more often associated with fluoxetine than with bupropion SR or placebo.

Similar differences between treatments were reported in two prospective clinical trials in which patients with antidepressant-associated sexual dysfunction were switched from an SSRI to bupropion.55,56 Sexual side effects resolved while antidepressant efficacy was maintained in both studies. In one study, bupropion SR was initiated prior to discontinuation of paroxetine, sertraline, fluoxetine, or venlafaxine while in the other, bupropion was initiated 2 weeks after discontinuation of fluoxetine. Both of these methods of switching from an SSRI to bupropion were generally well tolerated.

Conclusion

Health care providers increasingly recognize antidepressant-associated sexual dysfunction as a significant problem among some patients. Sound sexual function is important in maintaining the patient’s quality of life and self-esteem, preserving interpersonal relationships, and ensuring compliance with the antidepressant regimen. The introduction of new antidepressants augments the range of options for controlling or avoiding sexual dysfunction. In particular, the norepinephrine and dopamine reuptake inhibitor bupropion SR and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective at controlling depressive symptoms as are antidepressants associated with sexual dysfunction,57,58 but with a low incidence of this undesirable side effect. PP

References

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

2. Gitlin MJ. Effects of depression and antidepressants on sexual functioning. Bull Menninger Clin. 1995;59:232-248.

3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: A critical review. J Clin Psychopharmacol. 1999;19:67-85.

4. Croft H, Settle E, Houser T, et al. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther. 1999;21:643-658.

5. Coleman CC, Cunningham LA, Foster VJ, et al. Sexual dysfunction associated with the treatment of depression: A placebo-controlled comparison of bupropion sustained-release and sertraline treatment. Ann Clin Psychiatry. 1999;11:205-215.

6. Coleman CC, King BR, Bolden-Watson C, et al. A placebo-controlled comparison of the effects on sexual functioning of sustained-release bupropion and fluoxetine. Clin Ther. 2001;23:1040-1058.

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

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

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

10. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry. 2001;62(suppl 3):10-21.

11. Jamerson B, Ashton AD, Houser TL, et al. Antidepressant compliance and side effects: results from a patient survey. Poster presented at: the 154th Annual Meeting of the American Psychiatric Association; May 2001; New Orleans, LA.

12. Modell JG, Katholi C, Modell JD, et al. Comparative sexual side effects of SSRIs and bupropion. Clin Pharm Ther. 1997;61:476-487.

13. Montejo-Gonzalez 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;23:176-194.

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

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

16. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol. 2000;20:122-128.

17. Feiger A, Kiev A, Shrivastava RK, et al. Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry. 1996;57(suppl 2):53-62.

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

19. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance of male rats. Life Sci. 1989;45:1263-1270.

20. Rodriguez M, Castro R, Hernandez G, et al. Different roles of catecholaminergic and serotoninergic neurons of the medial forebrain bundle on male rat sexual behavior. Physiol Behav. 1984;33:5-11.

21. Nurnberg HG, Levine PE. Spontaneous remission of MAOI-induced anorgasmia. Am J Psychiatry. 1987;144:805-807.

22. Reimherr FW, Chouinard G, Cohn CK, et al. Antidepressant efficacy of sertraline: A double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry. 1990;51:18-27.

23. Patterson WM. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry. 1993;54:71.

24. Barton JL. Orgasmic inhibition by phenelzine. Am J Psychiatry. 1979;136:616-617.

25. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry. 1995;152:1514-1516.

26. Ferguson JM, Shrivastava RK, Stahl SM, et al. Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline. J Clin Psychiatry. 2001;62:24-29.

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

28. Balogh S, Hendricks SE, Kang J. Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry. 1992;53:212-213.

29. Shrivastava RK, Shrivastava S, Overweg N, et al. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1995;15:83-84.

30. Balon R. Intermittent amantadine for fluoxetine-induced anorgasmia. J Sex Marital Ther. 1996;22:290-292.

31. Masand PS, Reddy N, Gregory R. SSRI-induced sexual dysfunction successfully treated with amantadine. Depression. 1995;2:319-321.

32. Ashton AD, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 1998;59:112-115.

33. Labbate LA, Pollack MH. Treatment of fluoxetine-induced sexual dysfunction with bupropion: a case report. Ann Clin Psychiatry. 1994;6:13-15.

34. Bodkin JA, Lasser RA, Wines JD Jr, et al. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry. 1997;58:137-145.

35. Landén M, Bjorling G, Agren H, et al. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59:664-668.

36. Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. Depression. 1994;2:109-112.

37. Othmer E, Othmer SC. Effect of buspirone on sexual dysfunction in patients with generalized anxiety disorder. J Clin Psychiatry. 1987;48:201-203.

38. Fava M, Rankin MA, Alpert JE, et al. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychother Psychosom. 1998;67:328-331.

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

40. Hollander E, McCarley A. Yohimbine treatment of sexual side effects induced by serotonin reuptake blockers. J Clin Psychiatry. 1992;53:207-209.

41. Segraves RT. Treatment of drug-induced anorgasmia. Br J Psychiatry. 1994;165:554.

42. Feder R. Reversal of antidepressant activity of fluoxetine by cyproheptadine in three patients. J Clin Psychiatry. 1991;52:163-164.

43. McCormick S, Olin J, Brotman AW. Reversal of fluoxetine-induced anorgasmia by cyproheptadine in two patients. J Clin Psychiatry. 1990;51:383-384.

44. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol. 1995;18:320-324.

45. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand. 1996;93:69-70.

46. Cohen AJ, Bartlick BD. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24:139-143.

47. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry. 1999;60:260-261.

48. Reynolds RD. Sertraline-induced anorgasmia treated with intermittent nefazodone. J Clin Psychiatry. 1997:58:89.

49. Roeloffs C, Barlick B, Kaplan PM, et al. Methylphenidate and SSRI-induced sexual side effects. J Clin Psychiatry. 1996;57:548.

50. Michael A, O’Donnell EA. Fluoxetine-induced sexual dysfunction reversed by trazodone. Can J Psychiatry. 2000;45:847-848.

51. Clayton AH, McGarvey E, Warnock J, et al. Bupropion sustained-release as an antidote to SSRI-induced sexual dysfunction. Available at: www.nimh.nih.gov/ncdeu/abstracts2000/ncdeu169.cfm. Accessed March 25, 2002.

52. Keller Ashton A, Hamer R, Rosen RC. Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients. J Sex Marital Ther. 1997;23:165-175.

53. Goldbloom DS, Kennedy SH. Adverse interaction of fluoxetine and cyproheptadine in two patients with bulimia nervosa. J Clin Psychiatry. 1991;52:261-262.

54. Kavoussi RJ, Segraves RT, Hughes AR, et al. Double-blind comparison of bupropion sustained-release and sertraline in depressed outpatients. J Clin Psychiatry. 1997;58:532-537.

55. Walker PW, Cole JO, Gardner EA. Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J Clin Psychiatry. 1993;54:459-463.

56. Clayton AH, McGarvey EL, Abouesh AI, et al. Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. J Clin Psychiatry. 2001;62:85-190.

57. Mulrow CD, Williams JW, Madjukar T, et al. Treatment of Depression: Newer Pharmacotherapies. Rockville, Md: Agency for Health Care Research and Quality; February 1999: Publication no. 99-E014.

58. Geddes JR, Freemantle N, Jason J, et al. SSRIs versus other antidepressants for depressive disorder.The Cochrane Library. 2000 (4)CD002791. Oxford: Update Software.

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Anita H. Clayton, MD
 
Primary Psychiatry. 2003;10(1):55-61

 

Dr. Clayton is professor and vice chairin theDepartment of Psychiatric Medicine at the University of Virginia Health Systems in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer. No financial, academic, or other support was received for this work.

Please direct all correspondence to: Anita H. Clayton, MD, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22908-0623; Tel: 434-924-2241; Fax:?434-924-5149; E-mail: ahc8v@virginia.edu


 

Abstract

How can the occurrence of antidepressant-associated sexual dysfunction be minimized? In prospective studies, sexual dysfunction has been reported by up to 70% of patients using serotonergic antidepressants, which are associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or minimally affect serotonergic neurotransmission. Three approaches to managing antidepressant-associated sexual dysfunction include reduction or elimination of antidepressant doses suspected of causing sexual dysfunction, use of a second medication to reverse sexual dysfunction, or substitution of a second antidepressant not associated with sexual side effects. The introduction of new antidepressants augments the options for controlling or avoiding sexual dysfunction. For symptoms of depression, the norepinephrine and dopamine reuptake inhibitor bupropion sustained-release and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective as serotonergic antidepressants, but with a much lower incidence of sexual dyfunction.

Introduction

Clinically depressed individuals often suffer from sexual dysfunction, which can arise from numerous causes, including the depression itself, comorbid psychiatric or medical disorders, antidepressant therapy, and concomitant medications.1 A primary role of antidepressant therapy in the etiology of sexual dysfunction has become increasingly recognized since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.2 While SSRIs and other medications that enhance serotonergic function are most strongly associated with orgasm dysfunction,3-6 they may also be associated with disorders of other phases of the sexual response cycle, including desire and arousal.7-9 As data from well-controlled studies on the sexual side effects of SSRIs and other serotonergic antidepressants have accumulated over the last decade and a half, health care providers’ concern about these side effects and interest in exploring treatment strategies that minimize or eliminate sexual side effects have grown. This review, based on MEDLINE searches and systematic review of congress abstracts, considers clinical aspects, prevalence, and possible mechanisms of antidepressant-associated sexual dysfunction with a discussion of strategies to minimize the occurrence of this side effect.

Antidepressant-Associated Sexual Dysfunction

Clinical Consequences

Sexual dysfunction can adversely affect quality of life, self-esteem, and interpersonal relationships. These effects are of particular concern among patients with depression, in whom these issues may already be compromised. Moreover, antidepressant-associated sexual dysfunction may lead to medication noncompliance and premature discontinuation and thereby may increase the risk of relapse or recurrence of depression.10,11

In an open-label study of 1,022 patients with a mean 40 years of age, 59.1% reported antidepressant-associated sexual dysfunction.10 The study analyzed the following antidepressants: citalopram, paroxetine, venlafaxine, sertraline, fluvoxamine, fluoxetine, mirtazapine, nefazodone, amineptine, moclobemide, clomipramine, imipramine, maprotiline, phenelzine, and trazodone. Of those with sexual dysfunction attributed to antidepressants, 38.3% rated themselves as being concerned enough about sexual dysfunction to discontinue antidepressant therapy (Figure 1). Another 34.5% indicated that, although they did not intend to discontinue antidepressant therapy because of it, they and/or their partner were concerned or distressed about sexual dysfunction. That nearly 4 of 10 patients in this study were concerned enough about their sexual dysfunction to discontinue their antidepressant is worrisome in view of the fact that noncompliance with the therapeutic regimen may result in relapse or recurrence of depression.

In a patient survey (N=350) reported in 2001, 60% of patients indicated that they had stopped taking their prescribed antidepressant at one time or another, and 22% of patients indicated that they did not always take their antidepressant medication exactly as prescribed.11 Sexual dysfunction was one of the top five reasons for stopping medication or failing to use medication as prescribed. When asked to rate the impact of specific side effects, one fourth of the patients indicated that it would be extremely difficult to live with the side effects of orgasm dysfunction or erectile dysfunction.

Assessment

Across studies in which sexual dysfunction is a prospectively defined endpoint, the condition has been reported in up to 70% of patients using antidepressants such as SSRIs.9,12 Lower frequencies of sexual dysfunction are reported in studies in which sexual function was not objectively assessed or patients were not specifically queried.3,9 Variance in estimates of the prevalence of sexual dysfunction arises primarily from the fact that some studies specifically queried patients regarding sexual dysfunction whereas other studies relied on patients’ spontaneous reports. Because patients are usually reticent to initiate discussion about sexual dysfunction with their health care provider, reliance on spontaneous report of sexual dysfunction underestimates the commonality of the condition. This fact is illustrated by the results of a study (N=344) that assessed sexual dysfunction both via patients’ spontaneous reports and with a questionnaire. Whereas only 14% (28 of 200) of patients spontaneously reported sexual dysfunction, 58% (200 of 344 patients) subsequently reported sexual dysfunction when specifically asked.13

From a practical perspective, these results emphasize the importance of having health care providers discuss sexual function with their patients both before antidepressant therapy is initiated (to obtain a baseline measure) and during antidepressant therapy. Normalizing the issue by opening with an explanation of the frequency of sexual disorders in the general population and among depressed patients, as well as the frequency of sexual disorders associated with specific treatments for depression, can help remove the barriers to discussing sexual functioning with patients.1

Using the medical model to evaluate each stage of the sexual response cycle (desire, arousal, orgasm, resolution) or employing an assessment tool such as the Arizona Sexual Experiences (ASEX) Scale14 or the Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C)15 is also important in identifying and assessing sexual dysfunction. Once the presence of sexual dysfunction is confirmed, further evaluation is necessary to differentiate antidepressant-associated sexual dysfunction from sexual dysfunction that may be attributed to other causes.1 This evaluation should compare a sexual history with the current level of sexual functioning and should eliminate other contributing factors including comorbid medical or psychiatric conditions, medications, or substances of abuse. Because both erectile dysfunction and decreased libido commonly occur as symptoms of depression, it is important to determine the patient’s level of sexual functioning prior to the onset of depression to determine the relative contributions of depression and antidepressant therapy.1

Besides reliance on spontaneous reports, other factors that explain variability in estimates of the prevalence of sexual dysfunction include misattribution of depression-associated sexual dysfunction to antidepressant use, failure to account for other established correlates of decreased sexual function such as advancing age and physical illness, and variation among studies in the definition and measurement of sexual dysfunction. Moreover, many studies reporting on sexual dysfunction did not prospectively define it as an endpoint and were often not sufficiently powered to assess the influence of specific variables or interventions.

Several recent studies that have controlled for these methodological problems provide useful data on the prevalence of antidepressant-associated sexual dysfunction.4-6,16-18 The data from these recent studies are consistent in showing that the prevalence of sexual dysfunction differs by physiologic mechanism of the antidepressant: antidepressants affecting serotonergic neurotransmission are reliably associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or only minimally affect serotonergic neurotransmission. For example, in the first study to employ a validated rating scale to assess the effects of the 10 new-generation antidepressants on sexual dysfunction in a large population of patients, 37% of 6,297 patients consulting 1,100 primary care physicians in the United States, reported sexual problems associated with antidepressant use.18 The lowest rates of sexual dysfunction across all antidepressant groups were in patients treated with bupropion (22% and 25%, for the immediate-release and sustained-release [SR] forms, respectively) and nefazodone (28%). Patients treated with bupropion SR or nefazodone had a statistically significantly lower prevalence rate of sexual dysfunction than patients taking SSRIs (citalopram, fluoxetine, paroxetine, sertraline), or venlafaxine extended-release. The mean prevalence rate of presumed antidepressant-associated sexual dysfunction was 24.4% among a prospectively defined subpopulation of patients free from other probable causes of sexual dysfunction (ie, patients were 18–40 years of age, had no history of sexual side effects on previous antidepressants, had used their current antidepressant for at least 3 months, were not taking concomitant medications affecting sexual functioning, had no comorbid illness that would affect sexual functioning, and had a history of at least some sexual enjoyment). Patients treated with bupropion SR had the lowest prevalence (6.7%) of sexual dysfunction (Table 1).

Manifestations

The four phases of the sexual response cycle are desire, arousal (erection in men, engorgement and lubrication in women), orgasm, and resolution. The aspect of sexual functioning most often affected by serotonergic antidepressants is the ability to achieve orgasm, which is either delayed or does not occur in many patients treated with antidepressants.7 Because orgasm dysfunction, unlike other sexual problems such as decreased libido, rarely occurs as a manifestation of depression per se, it is more easily attributed to pharmacotherapy than are sexual symptoms that frequently occur as manifestations of depression.3 In addition to orgasm dysfunction, the serotonergic antidepressants have been linked to erectile dysfunction and decreased libido, although the data associating these sexual side effects with antidepressant therapy are less consistent.7

Mechanisms of Action

The mechanism of antidepressant-associated sexual dysfunction has not been determined. The range of possible mechanisms includes (1) nonspecific neurologic effects (eg, sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.8 It is probable that antidepressants impact several of these physiologic substrates of sexual function.

The association of some antidepressants and of depression itself with sexual dysfunction is not surprising in view of the fact that many of the neurotransmitter systems implicated in depression, including the serotonin, dopamine, and norepinephrine systems, are also implicated in control of sexual function. Animal research and data from studies in human subjects suggest that sexual behavior and function are enhanced by increases in brain dopaminergic function and inhibited by increases in brain serotonergic function.2,8,19,20 The latter observation is consistent with the association of serotonergic antidepressants with sexual dysfunction.

Management Strategies for Antidepressant-Associated Sexual Dysfunction

Four general approaches to managing antidepressant-associated sexual dysfunction have been adopted (Table 2). The first approach is deciding not to intervene for antidepressant-associated sexual dysfunction in the hope that spontaneous remission will occur. The second approach is to reduce or eliminate doses of the antidepressant suspected of causing sexual dysfunction. The third approach involves use of a second medication as an antidote to reverse sexual dysfunction. Finally, the fourth approach involves substitution of a second antidepressant unlikely to cause sexual side effects. Each of these strategies for managing antidepressant-associated sexual dysfunction is reviewed below.

No Intervention

Some health care providers decide not to intervene in the case of antidepressant-associated sexual dysfunction in the hope that sexual side effects may spontaneously remit over time.4 Spontaneous remission of antidepressant-associated sexual dysfunction has been reported in case studies.21,22 However, recent research suggests that it infrequently occurs within the first 6 months of initiation of therapy. In a prospective, open-label study of 1,022 outpatients taking antidepressants, 59% reported antidepressant-associated sexual dysfunction.10

Of the patients reporting sexual dysfunction, only 9.7% of them reported total improvement or spontaneous remission at the end of 6 months of antidepressant therapy; 79% of them reported no improvement. These data, suggesting that antidepressant-associated sexual dysfunction does not promptly remit, are consistent with data from the 16-week controlled comparison of sertraline and bupropion SR.16 In that study, sertraline-associated sexual dysfunction was observed at the end of the first treatment week (the initial assessment following the start of treatment) and was maintained throughout the 16-week treatment period. If spontaneous remission does not occur, failure to intervene may increase the likelihood of noncompliance with the antidepressant regimen—particularly among patients to whom sexual dysfunction is a significant concern.

Reducing or Eliminating Antidepressant Doses

Reducing the dose of antidepressant medication has been tried in attempts to ameliorate antidepressant-associated sexual dysfunction.8 This strategy has not been systematically assessed in controlled clinical studies but has been reported effective with an SSRI and a monoamine oxidase inhibitor.23,24 Depressive symptoms may reemerge with dose reduction.

Antidepressant drug holidays have also been employed as a strategy for reducing antidepressant-associated sexual dysfunction. Like the dose-reduction strategy, the efficacy of drug holidays in reducing antidepressant-associated sexual dysfunction has not been systematically studied. Positive results were obtained in one open-label, 30-patient study in which patients discontinued sertraline or paroxetine, but not fluoxetine, for the weekend. Discontinuation was associated with significant improvement in sexual functioning without a worsening of depressive symptoms.25

As drug holidays may result in antidepressant discontinuation syndrome and may provide a risk for relapse of depression, they are not an ideal strategy for most patients. Drug holidays may also limit patients’ spontaneity with respect to the timing of sexual activity. Furthermore, advising drug holidays for improvement of sexual dysfunction may encourage patients to be noncompliant with the treatment regimen during times when drug holidays are not advised or appropriate. Finally, in cases in which a drug holiday is effective in reducing sexual side effects, reinstatement of antidepressant therapy is likely to result in the reemergence of sexual dysfunction.

Reemergence of sexual dysfunction due to antidepressants was evaluated in a double-blind rechallenge study enrolling depressed patients who reported impairment in sexual function upon initiation of therapy with sertraline 100 mg OD.26 Patients discontinued sertraline for a 2-week period, and if their sexual functioning normalized during the 2-week period, were assigned to 8 weeks of double-blind treatment with sertraline 50 mg OD or the mixed serotonin antagonist/reuptake inhibitor nefazodone 100 mg BID. Beginning with the first week of reinstatement of sertraline therapy, sexual dysfunction reemerged. Whereas approximately 15% of patients were dissatisfied with sexual function before reinstatement of sertraline therapy, 50% were dissatisfied at week 1 of sertraline reinstatement. When doses were increased to 100 mg/day sertraline and 150 mg nefazodone BID during the second week of therapy, the proportion of sertraline-treated patients dissatisfied with sexual function increased to approximately 80%, which was consistently maintained through the remainder of the 8-week treatment period. These data suggest that drug holidays are not a viable long-term strategy for controlling antidepressant-associated sexual side effects, particularly for a chronic disease such as depression, which often requires life-long pharmacotherapy.

Adding an Antidote

Daily administration of pharmacotherapies that reverse sexual dysfunction and administration of antidotes acutely before sexual activity have also been tried. Agents used for this application are listed in Table 3.27-52 Although addition of an antidote can be successful in reducing the incidence of sexual side effects, it entails polytherapy, which relative to monotherapy increases the overall risk of side effects and drug interactions.

Of all of the agents administered as antidotes, only bupropion SR and buspirone have been demonstrated effective in placebo-controlled trials as well as open-label studies involving both sexes.27,32-37,51 Unlike some of the other augmentation therapies that have been tried, both bupropion SR and buspirone added to SSRI regimens appear to be well-tolerated. None of the other possible antidotes to antidepressant-associated sexual dysfunction have been evaluated in placebo-controlled studies. Evidence for their use is derived primarily from case reports and small, open-label investigations as follows:

• Several authors have reported that amantadine used for at least 2 days before sexual activity or on a regular basis reverses SSRI-associated sexual dysfunction.28-31 In a retrospective chart-review study involving records from 594 patients, amantadine was less effective than yohimbine at reversing SSRI-associated sexual dysfunction.52

• Sildenafil, which is currently approved only for management of erectile dysfunction in men, was reported in an open-label investigation to work as an antidote to antidepressant-induced sexual dysfunction in both men and women.38 Sildenafil is one of the only antidotes that can be taken on an as-needed basis shortly prior to sexual activity.

• Psychostimulants used intermittently or on a daily basis have been reported to be effective at reversing SSRI-associated sexual dysfunction.27,49 Possible drawbacks
of the use of psychostimulants include impairment of sexual function with increasing dose, the potential for abuse, and cardiovascular side effects.

• Ginkgo biloba has been reported in case reports and one uncontrolled study to counter SSRI-induced sexual dysfunction.27,46 As it is an over-the-counter herbal extract, its safety profile has not been assessed with the rigor that is applied to prescription medicines.

• Serotonin (5-HT)2 antagonists such as nefazodone and mirtazapine, as well as the 5-HT2 antagonist and antihistamine cyproheptadine, have been reported to be effective antidotes to antidepressant-associated sexual dysfunction.42-45,47,48 Cyproheptadine administered as daily therapy can interfere with the antidepressant efficacy of SSRIs.42,53 Administered acutely or chronically, it may also cause sedation, which can interfere with sexual function.

Substitution With an Antidepressant Unlikely to Cause Sexual Dysfunction

The development of new antidepressants with little or no adverse effects on sexual function has provided new opportunities for managing antidepressant-associated sexual dysfunction. Health care providers increasingly manage antidepressant-associated sexual dysfunction by starting new patients on an antidepressant shown to cause less sexual dysfunction than the SSRIs and venlafaxine. Similarly, in patients with antidepressant-associated sexual dysfunction, the sexually impairing antidepressant may be replaced with an antidepressant not associated with negative sexual side effects. These strategies have been shown to be effective with the nonserotonergic antidepressant bupropion SR as well as with the mixed serotonin antagonist/reuptake inhibitor nefazodone.7

Feiger and colleagues17 conducted a randomized, double-blind, parallel-group study to compare 6 weeks of treatment with nefazodone (n=71; mean modal end-of-treatment dose of 456 mg/day) and sertraline (n=72; mean modal end-of-treatment dose of 148 mg/day) with respect to efficacy, tolerability, and effects on sexual function. Sexual function was evaluated weekly via questionnaire. The results show that sertraline, but not nefazodone, significantly impaired sexual function, particularly among men. The following was noted among men during the last treatment week:

(1) 100% of those receiving nefazodone reported that they “fully enjoyed” or “sometimes enjoyed” sex compared with 57% of those receiving sertraline;

(2) 89% of those receiving nefazodone were at least moderately satisfied with sex compared with 50% of men receiving sertraline (Figure 2);

(3) 19% of those receiving nefazodone compared with 67% of those receiving sertraline reported difficulty with ejaculation; and

(4) 18% of those receiving nefazodone compared with 67% of those receiving sertraline indicated that they frequently, usually, or always took a long time to ejaculate.

Among women, 74% of those receiving nefazodone compared with 59% of those receiving sertraline were at least moderately satisfied with sex (Figure 2). Nefazodone-treated women achieved orgasm more easily and were more satisfied with the ability to achieve orgasm than were sertraline-treated women.

The effects on sexual function of bupropion SR have also been assessed in double-blind, head-to-head comparisons with SSRIs in patients with depression.4-6,16 In the first study, patients with moderate or severe depression received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks.16 To be included in the study, patients had to have normal sexual function (defined as absence of sexual arousal disorder, orgasm dysfunction, premature ejaculation, dyspareunia, or vaginismus) at baseline prior to the initiation of treatment, although sexual desire disorder associated with the depression could be present. The results demonstrate that the cumulative incidence of orgasm delay or failure was significantly (P<.001) greater among sertraline-treated patients (52%) than among bupropion SR-treated patients (8%), as was the overall incidence of sexual desire disorder (34% of sertraline-treated patients, 21% of bupropion-treated patients; P<.05) and the cumulative incidence of sexual arousal disorder (16% of sertraline-treated patients, 4% of bupropion SR-treated patients; P<.05). Consistent with these data, the percentage of patients satisfied with their sexual function at the end of the study increased substantially for bupropion SR (57% to 79%) but did not change for sertraline (57% to 58%). While bupropion SR had a better sexual tolerability profile than did sertraline, it conferred comparable efficacy for depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Severity, and the Clinical Global Impressions Scale for Improvement.54

These data were substantiated by two double-blind, placebo-controlled, 8-week studies that replicated the findings of the first study.4,5 The placebo-controlled studies also extended the earlier findings by demonstrating that the effects of bupropion SR on the incidence of orgasm dysfunction, sexual desire disorder, and sexual arousal disorder did not differ from those of placebo (with the exception of sexual arousal disorder on day 56 of treatment in one study4) in patients with major depression. In both of these studies as in the first one, differences between bupropion SR and sertraline were most marked for orgasm delay or failure, which of the sexual problems assessed was the most common one reported with sertraline therapy (Figure 3).

In a similar placebo-controlled study prospectively designed to compare the effects of bupropion SR (100–400 mg/day) with those of fluoxetine (10–60 mg/day) on sexual dysfunction, significantly more fluoxetine-treated patients experienced orgasm dysfunction beginning by the second treatment week and continuing throughout the study compared with bupropion SR- or placebo-treated patients (P<.001, Figure 4).6 This effect was observed both in patients defined as clinical responders (ie, those with a 50% decrease in total HAM-D scores during treatment) and in patients experiencing remission (ie, those with total HAM-D scores improved to less than 8). Worsened sexual functioning, decreased sexual desire, sexual arousal disorder, and dissatisfaction with sexual functioning were more often associated with fluoxetine than with bupropion SR or placebo.

Similar differences between treatments were reported in two prospective clinical trials in which patients with antidepressant-associated sexual dysfunction were switched from an SSRI to bupropion.55,56 Sexual side effects resolved while antidepressant efficacy was maintained in both studies. In one study, bupropion SR was initiated prior to discontinuation of paroxetine, sertraline, fluoxetine, or venlafaxine while in the other, bupropion was initiated 2 weeks after discontinuation of fluoxetine. Both of these methods of switching from an SSRI to bupropion were generally well tolerated.

Conclusion

Health care providers increasingly recognize antidepressant-associated sexual dysfunction as a significant problem among some patients. Sound sexual function is important in maintaining the patient’s quality of life and self-esteem, preserving interpersonal relationships, and ensuring compliance with the antidepressant regimen. The introduction of new antidepressants augments the range of options for controlling or avoiding sexual dysfunction. In particular, the norepinephrine and dopamine reuptake inhibitor bupropion SR and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective at controlling depressive symptoms as are antidepressants associated with sexual dysfunction,57,58 but with a low incidence of this undesirable side effect. PP

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