Concerns in Depression Treatment:
Sexual Dysfunction and Weight Gain
Primary Psychiatry. 2007;14(6):66-75
Dr. Clayton is David C. Wilson Professor in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia Health System in Charlottesville. Dr. Favit is director of medical strategy for US Medical Affairs at Bristol-Myers Squibb in Plainsboro, New Jersey.
Disclosures: Dr. Clayton is on the advisory boards of Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Fabre-Kramer, GlaxoSmithKline, Novartis, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and has received grants from BioSante, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, sanofi-aventis, and Wyeth. Dr. Favit owns stock in Bristol-Myers Squibb.
Please direct all correspondence to: Anita H. Clayton, MD, David C. Wilson Professor, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia Health System, P.O. Box 800623, Charlottesville, VA 22903; Tel: 434-924-2241; Fax: 434-243-4743; E-mail: firstname.lastname@example.org.
• Antidepressants are often associated with sexual dysfunction and weight gain.
• Clinicians should consider the risk for occurrence of these side effects when selecting an antidepressant.
Premature discontinuation of antidepressants is a prevalent and significant problem in the treatment of major depressive disorder (MDD). When a patient discontinues an antidepressant without consulting the clinician, the possibility of full remission of an acute depressive episode is seriously compromised and risk for subsequent recurrent episodes is increased. The primary reason patients discontinue antidepressant therapy without informing clinicians is a side effect that the patient attributes to the medication. Because all antidepressants have both short- and long-term side effects, this problem is of major concern both for patients with established chronic MDD who need longer term maintenance treatment as well as for those who are initiating acute therapy. Long-term side effects are most challenging to both the patient and clinician, especially during maintenance therapy. Sexual dysfunction and weight gain are two side effects particularly burdensome to patients. They tend to be long-term, may worsen with continued treatment, and are likely to have a significant impact on the patient’s quality of life. One or both of these adverse events are commonly associated with most antidepressants. Long-standing needs related to these side effects include physician-patient commitment to early and ongoing communication and assessment, timely intervention, and awareness of management options as well as the development of new, more tolerable therapies.
Major depressive disorder (MDD) is currently recognized as a chronic and recurring medical illness, characterized by periodic episodes of debilitating depression. Antidepressants offer a convenient and effective means of treatment for many patients with MDD. Numerous placebo-controlled clinical trials of first- and second-generation antidepressants have established that efficacy outcome is superior with active therapy compared with placebo.1-4
From a statistical standpoint, even among patients who have been adequately treated for a single episode of clinical depression, 50% will have another depressive episode, typically within 2 years of the first episode.5-6 Because antidepressant treatment reduces the incidence of depression relapse by up to 70% as well as lengthening the time between episodes for many patients, current guidelines now recommend continued treatment (ie, treatment for at least 4–6 months after completion of initial therapy).7-9
There is also a growing consensus among practitioners that longer treatment (>1 year) should be encouraged as further maintenance to achieve complete long-lasting depression remission, particularly in patients who are at high risk for relapse.8-13 Therefore, optimal treatment duration, along with the proven efficacy of several medication classes for MDD brings additional focus on the importance of treatment adherence.14
Premature Discontinuation: The Scope Of The Problem
A high prevalence of premature discontinuation among all major classes of antidepressants (Table 1)15-18 was demonstrated in four survey studies that utilized antidepressant use data through the year 2001. Data collected during the Medical Expenditure Panel Survey for 1996–2001 showed a near majority (42%) of adult patients discontinuing within the first 30 days of treatment, with only 27.6% continuing therapy for >90 days.18 Although such studies lack control groups, the surveyed patients were treated in community-based healthcare clinics and outside of the more limited perspective of the formal clinical study, with the advantage of the results being more likely to reflect common observations in practice settings.
Additional evidence from survey studies (data from over 7,900 patients accessed from a large health maintenance organization [HMO]) showed that the incidence of noncompliance (filling <4 prescriptions within 6 months of an initially prescribed drug) was as high as 80% among patients who were prescribed first-generation antidepressants, with better adherence (65.7%) among patients using second-generation and newer (eg, trazodone, fluoxetine) agents.19 Discontinuation incidence increased with the length of treatment, with >25% of patients discontinuing during the first month and almost half of the patients no longer taking an antidepressant by the third month of treatment.15-18 With newer drugs, 34% (226 of 672 patients) discontinued their antidepressant medication within the first 3 months of initiation (16% of patients switched to a new medication), with an additional 9% (62 of 672 patients) discontinuing between 4 and 6 months.16
Overall, these data are very disquieting, showing that 3–4 of 10 individuals who initiate antidepressant therapy for depression treatment discontinue medication within the first 30 days, and 25% to 45% of those who continue beyond 30 days stop medication during the following 30 days. In fact, a systematic overview of discontinuation data from 31 randomized, placebo-controlled clinical studies (4,410 patients) compared the frequency of antidepressant discontinuation (due to intolerance) in patients who had responded successfully to acute treatment. Patients were then randomly assigned to continuation therapy of the current agent, either selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs), or to placebo treatment. Prior efficacy notwithstanding, odds of discontinuation were significantly higher in the patients who continued to receive active treatment compared with those switched to placebo.8
Why Patients Quit
The primary reason why the majority of patients stop taking prescribed antidepressants during the first 3 months of treatment is the presence of one or more unwanted medication side effects. In a survey study, up to 84% of interviewed patients cited an adverse effect of medication, including drowsiness/fatigue, anxiety, headache, nausea, sexual dysfunction, feeling emotionally flat, insomnia, dizziness, dry mouth, weight gain, diarrhea, rash/itching, and blurred vision as a reason for treatment discontinuation.16 Several of these effects are short-term in nature (eg, headache, nausea, dizziness, dry mouth, diarrhea, rash) and discontinuation can be significantly reduced by educating patients about their temporal nature. Other effects including sexual dysfunction, weight gain, fatigue, and sedation arising or persisting after 3 months of therapy, significantly affect the individual compliance to antidepressant treatment.17,20-22 Clinicians face the quandary of comprehensively describing potential side effects of a long-term treatment without discouraging the patient from a treatment regimen that could lead to long-term remission of illness. Because the actual effectiveness of an antidepressant must take into account both efficacy and tolerability, the benefit of any therapy in relieving depression is necessarily tempered by the impact of side effects during prolonged treatment.
Although drowsiness and fatigue may significantly affect patient compliance and represent a major clinical concern, this article provides an overview of the clinical issues related to treatment-induced sexual dysfunction and weight gain.
Sexual function and body weight are recognized as integral and significant components of quality of life, particularly because of their large influence on a patient’s self-image and sense of personal and social well-being. As a result, potential drug-related changes in these areas justifiably promote reluctance to continue and, at times, even initiate treatment. This issue may be compounded for those patients for whom one or both problems are preexisting components of MDD and for those who perceive such change(s) as potentially worsening their depression.21,23 Both populations are likely to represent a majority of MDD patients.
Sexual dysfunction and weight gain side effects triggered by antidepressant therapy are challenging to reverse and often require medical management that includes approaches that may be outside of the clinician’s current expertise (eg, dietetics and nutrition in weight control). In addition, because these two side effects are not exclusive to psychotropic medications, the clinicians’s knowledge and understanding of the current literature is critical to their management. Given the complexity of the clinical issues revolving around premature discontinuation and current pharmacotherapy for depression, continued development of new, effective, and more tolerable therapy, particularly for longer term treatment of MDD, remains a significant need in this field.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) describes sexual dysfunction as “a disturbance in sexual desire and in the psychophysiological changes that characterize the sexual response cycle and cause marked distress and/or interpersonal difficulty.” Sexual dysfunction can be categorized as impairment that affects most frequently three of the four phases of the sexual response cycle: desire, arousal, orgasm, or resolution.24
Current evidence confirms that many antidepressants have a propensity to cause a variety of problems with sexual function that are typically experienced within 3 months of treatment initiation.25 In the HMO-based survey of SSRI-treated patients by Hu and colleagues,17 sexual dysfunction was the most commonly reported, bothersome (ie, “a lot bothersome” or “extremely bothersome”) side effect of medication in the patients surveyed. During the first 3 months, 34% of patients experienced drug-related sexual dysfunction, and 83% of these patients were still experiencing the effect at the end of 3 months.17 Overall, the most frequently reported sexual side effects associated with antidepressants are orgasmic dysfunction, particularly delayed or absent orgasm, and reduction in desire and arousal.26-32
Sexual function is based on multifactorial and interactive regulation involving, at least, neurogenic, psychogenic, vascular, and endocrine factors. Some antidepressants may directly or indirectly alter hormone activity and/or regulation. Many affect levels of nitric oxide, prolactin, and other molecular components that must be regulated for normal sexual function.33
Among the neurogenic factors, psychotropic agents including many antidepressants, affect regulation of sexual function. Adverse effects of these medications may contribute either nonspecifically, causing a general decrease in sexual interest and activity (eg, sedation), or specifically, by altering neurotransmission within the autonomic nervous system pathways that control sexual response.34-36 Working models of neurogenic regulation of sexual function postulate that neurotransmission (ie, both neurotransmitter and receptor functions) mediates central regulatory input at the level of the neural synapse34-36 through the monoamine transmitters serotonin and dopamine. In particular, the relative balance of these neurotransmitters at synapses in the central nervous system (CNS) is postulated to be a fundamental determinant of sexual function.29,37 An increase of serotonin and/or a decrease of dopamine levels are thought to induce a decrease of sexual function38 as demonstrated consistently through testing the effects of drugs altering serotonin or dopamine levels on sexual function in animals and man.38,39
Results from studies with psychotropic agents have contributed key components to working theories about sexual function. However, it is impossible to ascribe definitive cause-and-effect relationships between dysfunctions and specific antidepressant medications. Table 227,40-60 shows reported effects on the incidence of sexual dysfunction for several marketed antidepressants. High rates of sexual dysfunction are associated with all SSRIs (up to 73% of patients in naturalistic surveys), and the effects are reported to be strongly dose-related.31,42 Dysfunction in desire, arousal, and/or orgasm has been demonstrated with the use of all SSRIs, although the reported incidence varies for individual medications. In placebo-controlled trials in which change from baseline function was compared between treatment groups, sertraline, paroxetine, and fluoxetine were significantly associated with orgasmic problems in the treatment versus placebo group.43,44,49 The serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine, which have serotonergic action, also negatively affect sexual function.31,41,49,50,61
Although evidence is less extensive for the monoamine oxidase (MAO) inhibitors phenelzine and tranylcypromine, both (phenelzine to a much greater degree) are associated with a decline in sexual function, primarily having an effect on orgasmic capacity and, reportedly, in a dose-dependent fashion.55,57,62,63 Selegiline, an irreversible MAO-B inhibitor at low doses (5–10 mg/day) used in management of symptomatic Parkinson’s disease, demonstrated a negligible incidence of sexual dysfunction.64 Among five off-label studies of higher doses of selegiline (5–60 mg/day) used for MDD treatment, sexual dysfunction was reported in only one study. Based on spontaneous reports, incidence was low and similar to placebo.58,65-68 This finding is consistent with the predominantly dopaminergic effect of selegiline and relative absence of selective serotonergic activity compared with phenelzine and tranylcypromine.69,70 The selegiline transdermal system (STS), recently approved for the management of MDD symptoms, provides an antidepressant option that is not associated with sexual dysfunction.71-73 To assess STS effects on sexual function in four of five placebo-controlled studies, patients completed a 5-item rating scale to evaluate improvement in sexual interest, arousal, maintenance of interest, climax, and satisfaction after 6 or 8 weeks of treatment. A pooled data analysis of change from baseline scores in the five studies on STS revealed no difference in sexual dysfunction.
The atypical antidepressants nefazodone and mirtazapine, which exert a serotonergic antagonist effect by blocking serotonin (5-HT)2 and 5-HT3 receptors, have generally favorable safety profiles for sexual dysfunction47,74,75 and, in some studies, have been reported to reverse symptoms of sexual dysfunction experienced by patients treated with SSRIs.30,60,76,77 Bupropion, which also lacks serotonergic effects, has a favorable profile and may also improve sexual dysfunction when added to the treatment regimen in patients with antidepressant-associated sexual dysfunction.45,77-80
The definitive mechanisms responsible for antidepressant effects on sexual function are the subject of extensive ongoing research, and comprehensive information exists on this topic.35,36,81
Weight gain triggered by antidepressant therapy represents a considerable problem, especially if it is a significant increase in body weight (>7%) and unwarranted. Weight gain may remain unnoticed initially and progress slowly, but may eventually lead to significant negative impact on an patient’s perception and confidence with regard to one’s physical appearance. The possibility of weight gain is a common reason for rejection of antidepressant therapy,82 and patient surveys reveal that it is one of the more common reasons for premature discontinuation.15,16,83
Any patient who experiences weight gain during antidepressant treatment may be at increased risk for serious associated comorbidities, including insulin resistance, hypertension, and dyslipidemia.84 The potential for negative metabolic interactions mandates that any antidepressant treatment that may result in or maintain a patient’s body mass index (BMI) between overweight (25–29.9 kg/m2) and obesity (³30 kg/m2) be strictly avoided.85,86
Weight gain can be caused by increases in appetite or thirst, craving for “sweets” or carbohydrates, reduction in energy expenditure, or improvement of depressive symptoms as a result of the antidepressant effect. Similar to sexual dysfunction, mechanisms involved in these observed effects of antidepressant treatment are not well understood. In general, current hypotheses about weight control and energy use ascribe their regulation to interaction between the hypothalamus and a complex network of neurotransmitters, neuromodulators, cytokines, and hormones. Four biogenic amines—serotonin, histamine, dopamine, and noradrenaline—have documented CNS involvement in regulation of weight, energy, and appetite control.23,87,88 Thus, clinical effects of antidepressants on weight are viewed as arising in part from the neurogenic activity of these medications. In particular, agents that specifically promote serotonergic enhancement (particularly through increased activity at 5-HT1B and 5-HT2C receptors) are often associated with weight gain versus agents that promote noradrenergic activity with decreased appetite (and thus spur weight loss or no weight change). There is a paucity of data that detail the functional significance of each amine and its receptors, and this is an active area of current research.88
An overview of the observed effects of several antidepressants on body weight is provided in Table 3.23,47,54,59,82,89-107 For SSRIs, weight gain appears to be a class effect, although the magnitude of the effect varies among medications within the class. For many SSRIs, weight gain occurs only after long-term use (³6 months), although loss of weight sometimes occurs early in acute treatment. This dual aspect of SSRI effect on weight is not understood. Weight gain appears highest with paroxetine and the gain often begins early in treatment. The SNRIs venlafaxine and duloxetine, are not associated with weight gain in short-term treatment.81-88 However, duloxetine is associated with weight gain in long-term treatment,95 while no studies have been published on the long-term weight effects of venlafaxine treatment.
Among atypical antidepressants, mirtazapine use is associated with weight gain, which may be significant.82,104-106 In contrast, weight loss appears to be a common experience with bupropion use. Because weight loss is greater in patients with higher BMI, the utility of this drug in obesity research is under investigation.108,109 The effects of bupropion on metabolism are likely related to dopaminergic action, but are still poorly understood.37,82,92,102
There is an increased risk for weight gain with the irreversible MAO inhibitor phenelzine and to a lesser extent, tranylcypromine.54,98 The basis for these differences in effects among drugs in this class is unknown. However, tranylcypromine has an amphetaminelike structure, which could reduce its propensity to stimulate appetite. The irreversible MAO-B selegiline has not been associated with any effects on body weight as demonstrated in clinical trials with STS.59
Recent pre-clinical research has shown that antidepressants affect the expression of transcription-regulating molecules (eg, FOS (transcription factor), cAMP response element-binding) that lead to upregulation of cholesterol and fatty acid biosynthesis.110,111 Altered regulation of lipidogenic gene products may serve as part of antidepressant therapeutic effect as it relates to their effect on synaptogenesis. Because this activity may also explain certain metabolic effects of antidepressants, ongoing investigation will be fundamental in a further understanding of antidepressant-associated weight gain.88,112,113 Evidence does not show that antidepressant-associated weight gain is linked to an increase in serum glucose levels or insulin sensitivity, and the antidepressant may have a positive effect on these parameters even with associated weight gain. Little is known about antidepressant effects on other components of glucose homeostasis.
Treatment Choices For Avoiding Sexual Dysfunction And Weight Gain: Treatment Management
Prevention is the best strategy for reducing sexual dysfunction and weight gain side effects and ensuring treatment compliance. Treatment choices that may have an impact on sexual function must include knowledge and understanding of the patient’s history of sexual function and behavior as well as the level of satisfaction with current sexual function and relationships with partner(s). Issues related to the weight gain profile of antidepressants, such as predictors of weight gain, history of gain or loss, association with illness or smoking, and lifetime weight patterns as well as satisfaction with current weight and eating behaviors can be included in pre-treatment discussions with patients. The most appropriate antidepressant should be identified based on the patient’s presenting symptoms and medical history including predisposition and/or underlying conditions that can trigger or worsen a side effect. Patients have the highest chances for depression remission with early treatment, but also the highest risk for noncompliance during the acute treatment phase. Therefore, early alliance with the clinician is crucial.6 The importance of patient education, including information about the risks of premature discontinuation and involvement in treatment planning, is strongly supported by the results of the Collaborative Care randomized, controlled studies and several naturalistic studies.15,16,19-21,114,115 Education delivered prior to or early during the treatment course as well as rational therapy management based on realistic expectations and goals improves adherence to a medication regimen. Although it may not be possible to avoid all side effects, risk assessment, monitoring, and side effect management is essential.116 Therapeutic management of sexual dysfunction and weight-gain side effects resulting from antidepressant treatment include pharmacologic approaches targeting drug side effects, including switching the antidepressant, dose titration, and use of augmentation/antidotes. Nonpharmacologic approaches, although less common, include drug holidays and psychotherapy for sexual dysfunction as well as weight control education and weight gain programs. Each intervention has associated problematic features and ongoing studies continue to address the options that favor treatment outcome and improved quality of life.9,77,117 Among currently marketed antidepressants, duloxetine and bupropion have well-documented favorable tolerability profiles for both sexual dysfunction and weight change. Duloxetine is associated with a relatively low incidence of sexual dysfunction (eg, compared with SSRIs) and no weight gain in short-term trials.53 However, a pooled analysis of 10 studies showed weight gain in longer term treatment.88 Bupropion does not contribute to significant sexual dysfunction, is not associated with increases in weight, and may lead to weight loss in some patients.82,92
In a recent retrospective analysis of pharmacologic management strategies for antidepressant-related sexual dysfunction, the largest and most consistently positive effect in men was reported for the addition of sildenafil as an antidote. In the same study, switching to a different antidepressant (nefazodone) and/or the addition of bupropion or tadalafil as well as other augmentation approaches (eg, buspirone, olanzapine, granisetron, amantadine) appear to be of limited benefit.118 Both nefazodone and bupropion have been shown to improve sexual functioning in some patients with SSRI-associated existing sexual dysfunction.28,47,75,119
Although weight gain is best managed by switching antidepressants, alternative approaches, such as nutritional therapy, change in physical activity, and behavioral therapy, may be considered. Weight gain is particularly problematic for patients with reverse vegetative symptoms of appetite increase and/or weight gain associated with their depressive disorder. Such patients are likely to gain weight taking any antidepressant linked to this side effect.120 The optimum approach in such cases is to help the patient avoid weight gain during treatment.121 Himmerich and colleagues122 have shown that early weight increase (ie, during the first week of treatment) can serve as a reliable indicator to identify patients at risk for weight gain, thus providing one early treatment approach for estimating and circumventing further antidepressant effects on weight. Antidepressant treatment in this study was primarily non-SSRI, except for paroxetine (ie, TCA, SNRI, 5-HT2 receptor agonists, and lithium.)
The high incidence of antidepressant-associated sexual dysfunction and weight gain emphasizes that, despite the variety of antidepressants available, there is still an unmet need for efficacious and well-tolerated therapeutic agents.
Doapaminergic effects may mitigate against sexual dysfunction and weight gain. Among other antidepressants, bupropion and selegiline seem to have a minimal incidence of sexual side effects and weight gain. Similarly, STS, has been shown to be been well tolerated in clinical studies, with a very low incidence of sexual dysfunction and no evidence of weight gain.59 The low impact of STS on sexual function and body weight are consistent with the pharmacologic dopaminergic properties of selegiline, which potentiates dopaminergic activity as well as that of serotonin and noradrenaline, but with a low risk of dietary tyramine-induced hypertensive crisis that has been associated with other nonselective MAO inhibitors. In addition, no dietary modifications are required at the beginning of STS with the recommended dose of 6 mg/day. These efficacy and safety findings indicate that STS offers a unique therapeutic option, a transdermal MAO inhibitor not associated with sexual dysfunction or weight gain.
Antidepressants are often associated with sexual dysfunction and weight gain, and these poorly tolerated side effects are frequently the reason for early discontinuation of therapy. Selection of antidepressant treatment should evaluate the potential risk for onset of these side effects. In order to best enhance therapy adherence, clinicians and patients together should explore the side-effect profile of antidepressants, including sexual dysfunction and weight gain. Among antidepressants, bupropion and transdermal selegiline seem to have the most favorable tolerability profile for both sexual dysfunction and weight gain. A recently-approved transdermal MAO inhibitor, STS, is not associated with change in either sexual function or body weight and offers another alternative for antidepressant therapy without problematic long-term side effects. PP
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