Sexual functioning and quality of life in patients in remission from depression



b y S . H . K e n n e d y a n d S . R i z v i , C a n a d a

Sidney H. KENNEDY, MD, FRCPC
Sakina RIZVI, HBSc
Department of Psychiatry
University Health Network
University of Toronto
Toronto, CANADA

The adoption of remission as a clinical outcome in the treatment of major depressive disorder (MDD) has served to emphasize the important adverse consequences of residual symptoms following antidepressant treatment. These limitations are further underscored by differences between clinician and patient perceptions of remission, highlighting the need to extend outcome measures to include a broader evaluation of quality of life in patients who have received treatment for MDD. Sexual dysfunction is frequently reported as a symptom of MDD and more frequently occurs as a result of many current antidepressant treatments. The consequences of sexual dysfunction in many depressed patients include impairment of quality of life as well as treatment nonadherence and ultimately drug discontinuation. Many antidotes to alleviate antidepressant-induced sexual dysfunction have been advocated, but few have robust, randomized controlled trial evidence to support their recommendation. Where possible, monotherapy with an antidepressant that respects sexual function is a preferred strategy.
Medicographia. 2009;31:146-151. (see French abstract on page 151)

Keywords: sexual dysfunction; remission; quality of life; antidepressant; nonadherence; discontinuation

Remission: concept and reality

Remission in major depressive disorder (MDD) typically refers to symptom remission; that is, the near absence of all pre-existing symptoms endorsed on an established rating scale for depressive symptoms.1 Virtually all studies on the treatment of a major depressive episode utilize either the 17-item Hamilton Rating Scale for Depression (HAM-D17)2 or the Montgomery–Åsberg Depression Rating Scale (MADRS)3 to assess remission. For the HAM-D17, a score of 7 or less to connote remission has achieved the greatest acceptance.4 On MADRS, scores of 10 or less, or in some instances 12 or less, have been advocated to reflect remission.5,6
Evidence shows that there is variation among remission rates for different antidepressants and in different patient populations. Higher remission rates have been reported with venlafaxine (40%- 45%) compared with selective serotonin reuptake inhibitors (SSRIs; 35%-40%) in some,7,8 but not all, meta-analyses of randomized controlled trials.9,10 Patients in effectiveness trials typically achieve even lower rates of remission. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,11 only 28% of patients who received citalopram (SSRI) for up to 14 weeks met remission criteria.
Failure to achieve remission is associated with many adverse consequences, including high rates of recurrence, decreased work productivity, greater medical comorbidity, and an overall decrease in quality of life.4,12 Even patients treated to remission report a substantial burden of subthreshold or threshold symptoms: insomnia (44%), fatigue (38%), and anhedonia (27%) were the most prevalent residual symptoms in fluoxetine-treated remitters,13 while anxiety and loss of libido were also prevalent in other patient populations following remission.14,15 Although clinically meaningful, a limitation in the concept of remission is that it may not fully reflect the patient’s perspective regarding the balance between symptom change, side effect burden, and functional outcome. Patients reported “presence of positive mental health,” “return to one’s usual normal self,” and “return to usual level of functioning” as the three most important items in determining remission.16

Table I
Table I. Symptoms influencing psychiatrists’ antidepressant choice for outpatients.
Modified from reference 21: Zimmerman M, Posternak M, Friedman
M, et al. Which factors influence psychiatrists’ selection of antidepressants?
Am J Psychiatry. 2004;161:1285-1289. Copyright ©
2004, American Psychiatric Association

Quality of life as an expanded concept

By assessing a patient’s overall sense of satisfaction and personal wellbeing, quality of life measures reflect outcomes beyond symptom improvement. Patients with MDD may experience limitations in the areas of physical health, work efficiency, and social interactions. Measures have been developed for use across a wide range of disorders and populations (eg, Euro Quality of Life-5D, Short-Form 36-Item Questionnaire), across different psychiatric populations (eg, Social Adjustment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire), or specifically, in depressed patients (Social Adaptation and Self-Evaluation Scale).17 These scales have been valuable in demonstrating that psychosocial impairment persists in MDD even beyond remission,18,19 indicating that symptom improvement and quality of life do not necessarily improve at the same rate. When MDD patients were evaluated periodically over 5 years of treatment, marital and sexual satisfaction ratings were persistently lower compared with controls.20 Achieving symptomatic remission has to be partnered with minimal side effect burden to attain the best treatment outcome. This was recognized as an important issue by psychiatrists, who ranked sexual dysfunction as the highest consideration in prescribing an antidepressant, followed by weight gain and fatigue (Table I).21

Sexual dysfunction as a component
of remission and quality of life

In addition to sleep and alertness22 and neurocognitive symptoms,23 healthy sexual function is an important component of good quality of life, yet sexual dysfunction is a frequent consequence of antidepressant therapy,24-26 and is unacceptable tomany patients. In a large study involving over 6000 patients who received antidepressant therapy, 85% rated sexual functioning as “extremely important,” “very important,” or “important,” while only 3% felt it was “not important.”24 Unfortunately, sexual dysfunction is a relatively neglected aspect of both remission and quality of life, despite its simple measurement, high prevalence, and negative impact on treatment adherence.

Classification and measurement
The International Classification of Diseases and Related Health Problems–10th Edition (ICD-10)27 lists 10 forms of sexual dysfunction (Table II), which can be associated with physical or psychiatric conditions, medication treatments, or psychosocial factors. Sexual dysfunction in MDD typically involves problems with desire, arousal or orgasmic/ejaculatory function, and may occur across several of these areas. While the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition Text Revision (DSM IV-TR) does not explicitly include loss of sexual interest or desire as a core item, clinicians consider libido as a component of “diminished interest or pleasure,” and a single item on HAM-D17 captures desire or interest in sex as a component of overall symptom severity. However, this scale does not assess the broader impact of sexual dysfunction on quality of life.

Table II
Table II. Classification of sexual dysfunction according to the International Classification of Mental and Behavioural Disorders–10th edition. Based on data from reference 27.

The issue of measurement across the spectrum of sexual dysfunction is of particular importance when considering the adverse impact that SSRIs and other antidepressants can have on diverse ar areas of sexual function.28,29 Several easy to use sexual function scales are available (Arizona Sexual Experience Scale, Changes in Sexual Functioning Questionnaire, Psychotropic-Related Sexual Dysfunction Questionnaire, and the Sex Effects Scale).25 The importance of administering direct assessment scales is underscored by the findings that symptom reports increase twofold (69%) with direct questioning compared with reliance on spontaneous self-report (35%).30

Prevalence and risk factors
The prevalence of sexual dysfunction in the community is estimated to be approximately 20%- 30%31,32: a considerably higher prevalence rate of 50% or more has been reported in untreated depressed patients, and even higher rates are reported during antidepressant treatment.30 Risk factors for sexual dysfunction among psychiatric inpatients include: (i) history of physical, emotional, and sexual abuse; (ii) self-harm and depression; (iii) poor self-rated health and cardiopulmonary conditions; and (iv) use of antidepressants.33

Adherence and discontinuation
Treatment-emergent sexual dysfunction can cause significant distress to depressed patients, which adversely affects quality of life34 and leads to antidepressant nonadherence.35,36 Sexual dysfunction was the most bothersome side effect in a survey of more than 400 patients treated with SSRIs for approximately 3 months.37 Beside being a troublesome adverse event, sexual dysfunction is also one of the most common side effects leading to treatment discontinuation during short-term and long-term care.38,39 Further supporting this finding, Rosenberg and colleagues40 reported that 42% of men and 15% of women discontinue antidepressant treatment over perceived beliefs about sexual side effects.

Managing drug-induced sexual dysfunction in remitted patients

In order to reduce treatment nonadherence, several strategies can be used to mitigate treatmentemergent sexual dysfunction, including augmentation with an antidote, switching medications, or preferably prescribing an antidepressant with fewer sexual side effects in the first instance. Although primary prevention is the optimal solution, this is not always possible in the treatment of MDD. Several antidepressants are associated with treatmentemergent sexual dysfunction in less than 10% of patients, while others result in significant impairment in 30% or more patients (Table III).41 These differences have been linked to putative neurotransmitter and neuropeptide abnormalities associated with sexual dysfunction, and the beneficial or adverse effects of various antidepressants on these targets. Four mechanisms associated with drug-induced sexual dysfunction involve: (i) decreased dopaminergic activity; (ii) agonism of 5HT2 and 5HT3 receptors; (iii) blockade of adrenergic and cholinergic receptors; and (iv) inhibition of nitric oxide synthase. Various antidotes targeting one or more of these mechanisms have been advocated to mitigate these adverse effects.

Antidotes to mitigate sexual dysfunction
Enhancement of dopaminergic activity
Bupropion, psychostimulants, and amantadine have all been evaluated as treatments to relieve sexual dysfunction. In two out of three bupropion add-on studies, a dose of 150 mg versus placebo failed to improve sexual dysfunction associated with SSRIs,42,43 although augmentation with bupropion SR 150 mg twice daily was significantly better than placebo in improving desire and frequency of sexual activity in remitted depressed patients on SSRI therapies.44 It was also observed in an open-label augmentation study that bupropion not only improved sexual dysfunction in venlafaxine-treated patients, but also increased blood levels of venlafaxine approximately threefold.45
Stimulants such as methylphenidate have also been advocated to treat sexual dysfunction on the basis of their prodopaminergic effects. Although augmentation of antidepressant monotherapy with sustained release methylphenidate did not signifi- cantly enhance depression outcomes, there was a significant improvement in sexual function, as well as apathy and fatigue, compared with placebo.46 In clinical practice, other stimulants are used to enhance sexual function (dextroamphetamine, modafanil), but there are no randomized-controlled trials to support these recommendations. On a cautionary note, various dopamine agonists used to treat Parkinson’s disease (pramipexole, ropinirole, and pergolide) have been associated with pathological hypersexuality.47

Table III
Table III. Frequency of sexual dysfunction during antidepressant treatment with different antidepressant medications. Based on data from reference 41.

Antagonism of 5HT2 and 5HT3 receptors or agonism of 5HT1A receptors
Several antidepressants are known to display antagonist effects at 5HT2 or 5HT3 receptors. In the case of mirtazapine, there was found to be no advantage over placebo when the drug was added to fluoxetine in depressed women experiencing druginduced sexual dysfunction.48 There is preliminary evidence that mirtazapine added to duloxetine improves duloxetine-induced sexual dysfunction,49 and anecdotal support for cyproheptadine, a 5HT2 antagonist, particularly for anorgasmia,50,51 although granisetron, a 5HT3 antagonist, did not offer any advantage over placebo.52
The potentially beneficial antagonism of 5HT2A and 5HT2C receptors by atypical antipsychotics is countered by other mechanisms likely to increase serotonergic output and exacerbate sexual dysfunction. Despite the increasing use of “atypicals” such as risperidone, olanzapine, aripiprazole, quetiapine, and ziprasidone to treat patients with mood disorders, only minimal attention has been paid to sexual function. There was found to be no significant advantage of olanzapine versus placebo in reversing antidepressant-induced side effects,48 and contradictory findings were reported in two small openlabel studies using risperidone: a reduction in sexual function in one study and potentially beneficial effects in the other.53,54 The only systematic comparison of sexual dysfunction across atypical antipsychotics was performed in a large cross-sectional study involving more than 600 schizophrenia patients. Sexual dysfunction was reported in 43% of patients receiving risperidone, 35% on olanzapine, and 18% on quetiapine.55 Differences in diagnosis, underlying neurotransmitter function, dosing of atypical antipsychotics, and baseline sexual function limit the generalizability of these findings to the MDD population. Several agents with 5HT1A agonist properties have been evaluated as antidotes for sexual dysfunction. The anxiolytic, buspirone, has been shown to improve SSRI-induced sexual dysfunction, with more pronounced effects in women than men.56 Though flibanserin failed to demonstrate antidepressant efficacy, this 5HT1A agonist and 5HT2A antagonist with minimal DA4 agonist effects57 has been evaluated for the treatment of Hypoactive Sexual Desire Disorder in women, with positive results.58 VML-670 is a novel 5HT1A agonist with weak 5HT1D agonist properties. It was not superior to placebo in overall improvement of sexual dysfunction in previously depressed male and female patients.59
_ Blockade of adrenergic and cholinergic receptors
Yohimbine is an á-adrenergic agonist with favorable anecdotal evidence about its role in treating sexual dysfunction, but negative results under placebo- controlled conditions.48 Bethanecol has mixed central and peripheral cholinergic and adrenergic effects. It was effective in reversing clomipramineinduced ejaculatory delay under placebo-controlled conditions.60
_ Inhibition of nitric oxide synthase
The largest trials and most robust evidence for reversal of SSRI-induced sexual dysfunction involve treatment with sildenafil, the prototypic phosphodiesterase inhibitor. Sildenafil in doses of 25-100 mg has been shown to significantly enhance sexual function in both men61,62 and women63 treated to remission with SSRIs. Preliminary evidence also supports the role of tadalafil in reversing SSRI-induced sexual dysfunction in both men64 and women.65

Comparison of sexual dysfunction across antidepressant monotherapies
Sexual dysfunction is a significant problem with first generation monoamine oxidase inhibitors and tricyclic antidepressants, although other adverse effects have been of much greater clinical concern.
The consensus from a series of well-designed comparative studies is that up to 60% of patients receiving SSRIs report some form of treatmentemergent sexual dysfunction.24,28,66-71 All of the SSRIs have been associated with delayed or absent orgasm/ ejaculation, and in some instances, a reduction in libido and arousal.28,72,73
Similar rates of sexual dysfunction have been reported with serotonin norepinephrine reuptake inhibitors,68,74 although some evidence supports a lower rate with duloxetine, desvenlafaxine, and milnacipran, potentially related to greater noradrenergic blockade.75-77 Reboxetine is the only second generation norepinephrine receptor inhibitor, and is not widely available as an antidepressant. Nevertheless, it is associated with a relatively favorable sexual function profile compared with SSRIs.78
Among antidepressant monotherapies with the least likelihood of inducing sexual dysfunction, other variables beyond efficacy need to be considered. In the case of mirtazapine, switching to this from an SSRI resulted in lower rates of sexual dysfunction,79 but other adverse effects including weight gain and daytime sedation resulted in high rates of discontinuation.48 Nefazodone, a 5HT2 receptor antagonist and norepinephrine reuptake inhibitor, was relatively sparing of sexual function,80 but is now largely unavailable because of hepatotoxicity concerns.81 Bupropion, with its synergistic effects on dopamine and norepinephrine systems, results in less sexual dysfunction than SSRIs5,82 or venlafaxine.74 Similarly, moclobemide, a reversible inhibitor of monoamine oxidase A, has a favorable impact on sexual dysfunction, although it is not generally considered to be a first-line antidepressant.28,83,84
Agomelatine, a novel antidepressant with direct agonist effects on the melatonergic MT1 and MT2 receptors, as well as 5HT2C antagonist properties,85 has favorable effects on sexual function. Both mechanisms may synergistically account for its lack of sexual dysfunction, since agomelatine exerts putative antagonistic effects on 5HT2 receptors, which are in turn involved in sexual behaviour.86 In addition to antidepressant efficacy,87-89 agomelatine has been evaluated in depressed patients and healthy volunteers with sexual function as a primary outcome measure.5,90 Among sexually active remitted patients, there was significantly less treatmentemergent sexual dysfunction in patients receiving agomelatine compared with venlafaxine, specifically in the domains of sexual drive/desire in men and orgasm in women. This was illustrated by significantly greater deteriorations on the Sex Effects scale with venlafaxine for sexual drive/desire in men and orgasm in women (an approximately fivefold difference compared with agomelatine for both).5 In other agomelatine trials in which the Arizona Sexual Experience Scale was used, the rate of sexual dysfunction with agomelatine was comparable to or lower than that reported in the placebo group. These results are supported by a study carried out in healthy male volunteers who were randomized to receive agomelatine, paroxetine, or placebo for 8 weeks. The percentage of volunteers who experienced severe or moderate sexual dysfunction was under 5% for agomelatine, 62% for paroxetine, and 0% for placebo.90

Conclusion

The narrow clinical concept of remission, while valuable in a number of ways, fails to capture the broader domains associated with good quality of life. Healthy sexual function is an important outcome for patients with MDD, yet the majority of currently prescribed antidepressants induce or exacerbate sexual dysfunction. While there are various pharmacological approaches to mitigate drug-induced sexual dysfunction, prescribing a first-line antidepressant treatment that respects sexual function is a preferred approach. _

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FONCTION SEXUELLE ET QUALITÉ DE VIE DES PATIENTS APRÈS RÉMISSION D’UNE DÉPRESSION

L’ adoption de la rémission comme critère clinique dans le traitement des troubles dépressifs majeurs (TDM) a permis de souligner l’importance des conséquences négatives des symptômes résiduels après un traitement antidépresseur, comme le montrent les différences de perception de la rémission entre les médecins et les patients. Il est donc nécessaire d’élargir les critères d’évaluation afin de mieux mesurer la qualité de vie des patients qui ont été traités pour des TDM. Les troubles sexuels sont souvent rapportés comme symptômes du TDM et sont plus souvent encore la conséquence de nombreux traitements antidépresseurs actuels. Pour beaucoup de patients dépressifs, la dysfonction sexuelle entraîne une détérioration de la qualité de vie, une non observance du traitement puis son arrêt. De nombreux antidotes ont été proposés pour soulager les troubles sexuels dus aux antidépresseurs, mais très peu peuvent être recommandés sur la base d’études contrôlées randomisées fiables. La meilleure stratégie consiste donc dans la prescription d’une monothérapie (un seul antidépresseur) qui respecte la fonction sexuelle.