《气味科学中的健康密码》课程教学阅读材料：Rosa damascena oil improves SSRI-induced sexual dysfunction in male patients suffering from major depressive disorders：results from a double-blind, randomized, and placebo-controlled clinical trial

Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research ORIGINAL RESEARCH Rosa damascena oil improves SSRl-induced sexual dysfunction in male patients suffering from major depressive disorders:results from a double-blind, randomized,and placebo-controlled clinical trial This article was published in the following Dove Press journal Neuropsychiatric Disease and Treatment 9 March 2015 Number of times this article has been viewed Vahid Farnia' Background:A substantial disadvantage of psychopharmacological treatment of major Mehdi Shirzadifar2 depressive disorder(MDD)with selective serotonin-reuptake inhibitors(SSRIs)is the impact Jalal Shakeri' on sexual dysfunction.The aim of the present study was to investigate whether the oil of Rosa Mansour Rezaei3 damascena can have a positive influence on SSRI-induced sexual dysfunction(SSRI-I SD)of Hafez Bajoghli45 male patients who are suffering from MDD and are being treated with SSRIs Edith Holsboer-Trachslers Method:In a double-blind.randomized,and placebo-controlled clinical trial.a total of 60 male Serge Brand6.7 patients treated with an SSRI and suffering from MDD(mean age =32 years)and SSRI-I SD were randomly assigned to take either verum(R.damascena oil)or a placebo.Patients completed ISubstance Abuse Prevention self-ratings of depression and sexual function at baseline.at 4 weeks later,and at the end of the Research Center,Psychiatry Department,Kermanshah University study.8 weeks after it started. of Medical Sciences,Kermanshah,Iran; Results:Over time,sexual dysfunction improved more in the verum group than in the control Student Research Center,Psychiatry Department,Kermanshah University group.Improvements were observed in the verum group from week 4 to week 8.Self-rated of Medical Sciences,Kermanshah symptoms of depression reduced over time in both groups,but did so more so in the verum Iran;Department of Statistics and group than in the control group. Epidemiology,Kermanshah University of Medical Sciences,Kermanshah. Conclusion:This double-blind,randomized,and placebo-controlled clinical trial showed that Iran:ranian National Center for the administration of R.damascena oil ameliorates sexual dysfunction in male patients suffer- Addiction Studies,Iranian Institute ing from both MDD and SSRI-I SD.Further,the symptoms of depression reduced as sexual for Reduction of High-Risk Behaviors Tehran University of Medical Sciences, dysfunction improved. Tehran.Iran;SASEAN Institute Keywords:major depressive disorder,Rosa damascena oil,sexual dysfunction,selective for Health Development,Mahidol University,Nakhon Pathom,Thailand; serotonin-reuptake inhibitors,SSRI-induced sexual dysfunction Psychiatric Clinics of the Center for Affective,Stress and Sleep Disorders, Psychiatric Hospital of the University Introduction of Basel,Basel,Switzerland;7Sport Among psychiatric disorders,major depressive disorders(MDDs)merit particular Science Section,Department of Sport, Exercise and Health,University of attention because they are among the most prevalent lifetime psychiatric disorders.Not Basel,Basel.Switzerland surprisingly,Murray and Lopez,on the basis of data obtained by using the Disability- Adjusted-Life-Years instrument to assess"the sum [of the]years lost due to premature mortality and years lived with disability adjusted for severity",?estimated that MDD will be the third leading cause ofburden worldwide by 2020,with chronic lifelong risk Correspondence:Serge Brand for recurrent relapse,high morbidity,comorbidity,and mortality.The core symptom Center for Affective,Stress and Sleep of MDD is the loss of interests and pleasure in activities that were otherwise interest- Disorders,Psychiatric Hospital of the University of Basel,Wilhelm Klein-Strasse ing and pleasant to the patient.This holds particularly true for sexual function.Not 27,4012 Basel,Switzerland surprisingly,patients suffering from MDD report higher rates of sexual dysfunction Te+41613255l14 Fax+41613255513 than do members of a healthy population.Accordingly,sexual dysfunction is very Email serge.brand@upkbs.ch often observed among patients suffering from MDD. Neuropsychiatric Disease and Treatment 2015:1I625-635 625 Dovepress httpolldx.doi.org/10.2147/NOT578694

© 2015 Farnia et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Neuropsychiatric Disease and Treatment 2015:11 625–635 Neuropsychiatric Disease and Treatment Dovepress submit your manuscript | www.dovepress.com Dovepress 625 Origi n al R esearch open access to scientific and medical research Open Access Full Text Article http://dx.doi.org/10.2147/NDT.S78696 Rosa damascena oil improves SSRI-induced sexual dysfunction in male patients suffering from major depressive disorders: results from a double-blind, randomized, and placebo-controlled clinical trial Vahid Farnia1 Mehdi Shirzadifar2 Jalal Shakeri1 Mansour Rezaei3 Hafez Bajoghli4,5 Edith Holsboer-Trachsler6 Serge Brand6,7 1 Substance Abuse Prevention Research Center, Psychiatry Department, Kermanshah University of Medical Sciences, Kermanshah, Iran; 2 Student Research Center, Psychiatry Department, Kermanshah University of Medical Sciences, Kermanshah, Iran; 3 Department of Statistics and Epidemiology, Kermanshah University of Medical Sciences, Kermanshah, Iran; 4Iranian National Center for Addiction Studies, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran; 5 ASEAN Institute for Health Development, Mahidol University, Nakhon Pathom, Thailand; 6 Psychiatric Clinics of the Center for Affective, Stress and Sleep Disorders, Psychiatric Hospital of the University of Basel, Basel, Switzerland; 7Sport Science Section, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland Background: A substantial disadvantage of psychopharmacological treatment of major depressive disorder (MDD) with selective serotonin-reuptake inhibitors (SSRIs) is the impact on sexual dysfunction. The aim of the present study was to investigate whether the oil of Rosa damascena can have a positive influence on SSRI-induced sexual dysfunction (SSRI-I SD) of male patients who are suffering from MDD and are being treated with SSRIs. Method: In a double-blind, randomized, and placebo-controlled clinical trial, a total of 60 male patients treated with an SSRI and suffering from MDD (mean age =32 years) and SSRI-I SD were randomly assigned to take either verum (R. damascena oil) or a placebo. Patients completed self-ratings of depression and sexual function at baseline, at 4 weeks later, and at the end of the study, 8 weeks after it started. Results: Over time, sexual dysfunction improved more in the verum group than in the control group. Improvements were observed in the verum group from week 4 to week 8. Self-rated symptoms of depression reduced over time in both groups, but did so more so in the verum group than in the control group. Conclusion: This double-blind, randomized, and placebo-controlled clinical trial showed that the administration of R. damascena oil ameliorates sexual dysfunction in male patients suffer￾ing from both MDD and SSRI-I SD. Further, the symptoms of depression reduced as sexual dysfunction improved. Keywords: major depressive disorder, Rosa damascena oil, sexual dysfunction, selective serotonin-reuptake inhibitors, SSRI-induced sexual dysfunction Introduction Among psychiatric disorders, major depressive disorders (MDDs) merit particular attention because they are among the most prevalent lifetime psychiatric disorders.1 Not surprisingly, Murray and Lopez, on the basis of data obtained by using the Disability￾Adjusted-Life-Years instrument to assess “the sum [of the] years lost due to premature mortality and years lived with disability adjusted for severity”,2 estimated that MDD will be the third leading cause of burden worldwide by 2020, with chronic lifelong risk for recurrent relapse, high morbidity, comorbidity, and mortality.1 The core symptom of MDD is the loss of interests and pleasure in activities that were otherwise interest￾ing and pleasant to the patient. This holds particularly true for sexual function. Not surprisingly, patients suffering from MDD report higher rates of sexual dysfunction than do members of a healthy population.3–7 Accordingly, sexual dysfunction is very often observed among patients suffering from MDD. Correspondence: Serge Brand Center for Affective, Stress and Sleep Disorders, Psychiatric Hospital of the University of Basel, Wilhelm Klein-Strasse 27, 4012 Basel, Switzerland Tel +41 61 325 51 14 Fax +41 61 325 55 13 Email serge.brand@upkbs.ch Journal name: Neuropsychiatric Disease and Treatment Article Designation: Original Research Year: 2015 Volume: 11 Running head verso: Farnia et al Running head recto: Rosa damascena oil for male SSRI-induced sexual dysfunction DOI: http://dx.doi.org/10.2147/NDT.S78696

Farnia et al Dovepress There are several options for the treatment of MDD. occurs through several brain pathways,it is assumed that These include psychotherapy,physical activity,-13 elec- at least one pathway that involves increases in serotonin troconvulsive therapy,45 and psychopharmacotherapy (5-HT)leads to an inhibition of the ejaculatory reflex by (antidepressants).6In this paper,we focus on the psychop- serotonergic neurotransmission30 and stimulation of post- harmacological treatment of MDD. synaptic 5-HT2 and 5-HT3 receptors;31322)decreases in the The explanation for the occurrence of MDD in terms of release of dopamine and norepinephrine from the substantia monoamine deficiency(depletion of serotonin,norepineph-nigra have been observed;31323)the inhibition of nitric oxide rine,and dopamine in the central nervous system)7argues for synthase has been observed;33 4)increases in corticolimbic treatment with antidepressants(selective serotonin-reuptake 5-HT levels seem to be strongly associated with reductions inhibitors [SSRIs],selective serotonin-norepinephrine in sexual desire,ejaculation,and orgasm.3435 It is therefore reuptake inhibitors,noradrenergic and specific serotonergic perhaps unsurprising that sexual dysfunction is observable in antidepressants,and serotonin antagonist reuptake inhibi- 30%-80%of patients after they begin taking SSRIs.2242735. tors)that should increase monoamine levels.819 However, Again unsurprisingly,sexual dysfunction seems to be one of several studies indicate that the efficacy of antidepressants the main reasons for discontinuing the intake of SSRIs,37-39 is limited:a therapeutic effect is observed at most in 70% a pattern observed in up to 90%of patients treated with of patients suffering from MDD20 with maximum adherence SSRIs.40 Therefore,it is important to identify strategies that of 50%4 weeks after starting treatment.21 This is probably can alleviate SSRI-I SD.25.37.38.40 due to the 2-week or greater time lag for antidepressant to SSRI-I SD is regarded as such a serious disability prob- take effect,20 and is probably also due to various adverse ably because for humans,sexual activity and sexual intimacy side effects such as weight gain,dry mouth,and sexual may serve at least four distinct goals:1)exploring one's dysfunction.22 partner's values;2)reproduction;3)pair-bonding and pair This last side effect,SSRI-induced sexual dysfunction stabilization;4 and 4)joy 42-5 or quality of life.25.45 Among (SSRI-I SD),is considered one of its most disturbing and humans,sexual activity within couples usually signifies disruptive side effects.2-25 Indeed,SSRIs can have a nega- exclusivity,intimacy,and bond-reinforcing behavior.4 The tive impact on any or on all phases of the sexual cycle by sexual activity and sexual intercourse in heterosexual couples causing a decreased libido,an impairment in arousal,and can occur under many different conditions:1)before and erectile dysfunction;SSRIs are most commonly associated after the female's fertile phase(ovulation);2)during preg- with delayed ejaculation and absent or delayed orgasm.26On nancy;and 3)in females,during post-menopausal stage,thus the basis of a meta-analysis of 31 studies,including a total of indicating that,for heterosexual couples,sexual intercourse 10,130 patients,Serretti and Chiesa27 concluded that the total must serve needs beyond mere reproduction.Further,unlike rate ofsexual dysfunction associated with SSRIs ranged from with bonobos and chimpanzees,who belong to the two 25.8%to 80.3%and was significantly higher than the placebo species closest to humans and who are sexually active in rate of 14.2%.More specifically,Clark et al4 reported that the presence and sight of other group members,humans, the SSRIs citalopram,fluoxetine,paroxetine,and sertraline in all cultures and regardless of sexual orientation,engage and the SNRI venlafaxine were associated with significantly in sexual relations in private and beyond the view of others; greater rates(70%80%)ofreported total sexual dysfunction, these practices further reinforce exclusive intimacy between including negative impacts on desire,arousal,and orgasm, partners.Given the exclusivity of sexual activity and its than was the placebo.In this regard,Garlehner et al2s found importance to bonding and bonding quality,it is not surpris- that paroxetine,citalopram,and venlafaxine,when compared ing its impairment is regarded as distressing and disturbing with other antidepressants(fluoxetine,fluvoxamine,nefa-both for the individual and for couple-related quality of life. zodone,sertraline),were associated with a higher rates of This holds particularly true for patients suffering from MDD, reported sexual dysfunction,such as complaints of erectile even during the recovery phase.For example,Clayton et al2s dysfunction in men and decreased vaginal lubrication in reported that among patients suffering from MDD,the use women.In addition,citalopram was associated with reduced of SSRIs was associated with sexual dysfunction and hence sperm quality.29 had further implications for compliance and distress for the How can SSRI-I SD be explained?In the absence of patient and her or his sexual satisfaction. a conclusive neurophysiological rationale,the following Overall,the evidence strongly supports the view that hypotheses are advanced:1)whereas sexual dysfunction among humans,sexual activity has importance beyond mere 626 submit your manuse Neuropsychiatric Disease and Treatment 2015:II Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 626 Farnia et al There are several options for the treatment of MDD. These include psychotherapy,8,9 physical activity,1–13 elec￾troconvulsive therapy,14,15 and psychopharmacotherapy (antidepressants).16 In this paper, we focus on the psychop￾harmacological treatment of MDD. The explanation for the occurrence of MDD in terms of monoamine deficiency (depletion of serotonin, norepineph￾rine, and dopamine in the central nervous system)17 argues for treatment with antidepressants (selective serotonin-reuptake inhibitors [SSRIs], selective serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, and serotonin antagonist reuptake inhibi￾tors) that should increase monoamine levels.18,19 However, several studies indicate that the efficacy of antidepressants is limited; a therapeutic effect is observed at most in 70% of patients suffering from MDD20 with maximum adherence of 50% 4 weeks after starting treatment.21 This is probably due to the 2-week or greater time lag for antidepressant to take effect,20 and is probably also due to various adverse side effects such as weight gain, dry mouth, and sexual dysfunction.22 This last side effect, SSRI-induced sexual dysfunction (SSRI-I SD), is considered one of its most disturbing and disruptive side effects.23–25 Indeed, SSRIs can have a nega￾tive impact on any or on all phases of the sexual cycle by causing a decreased libido, an impairment in arousal, and erectile dysfunction; SSRIs are most commonly associated with delayed ejaculation and absent or delayed orgasm.26 On the basis of a meta-analysis of 31 studies, including a total of 10,130 patients, Serretti and Chiesa27 concluded that the total rate of sexual dysfunction associated with SSRIs ranged from 25.8% to 80.3% and was significantly higher than the placebo rate of 14.2%. More specifically, Clark et al24 reported that the SSRIs citalopram, fluoxetine, paroxetine, and sertraline and the SNRI venlafaxine were associated with significantly greater rates (70%–80%) of reported total sexual dysfunction, including negative impacts on desire, arousal, and orgasm, than was the placebo. In this regard, Garlehner et al28 found that paroxetine, citalopram, and venlafaxine, when compared with other antidepressants (fluoxetine, fluvoxamine, nefa￾zodone, sertraline), were associated with a higher rates of reported sexual dysfunction, such as complaints of erectile dysfunction in men and decreased vaginal lubrication in women. In addition, citalopram was associated with reduced sperm quality.29 How can SSRI-I SD be explained? In the absence of a conclusive neurophysiological rationale, the following hypotheses are advanced: 1) whereas sexual dysfunction occurs through several brain pathways, it is assumed that at least one pathway that involves increases in serotonin (5-HT) leads to an inhibition of the ejaculatory reflex by serotonergic neurotransmission30 and stimulation of post￾synaptic 5-HT2 and 5-HT3 receptors;31,32 2) decreases in the release of dopamine and norepinephrine from the substantia nigra have been observed; 31,32 3) the inhibition of nitric oxide synthase has been observed;33 4) increases in corticolimbic 5-HT levels seem to be strongly associated with reductions in sexual desire, ejaculation, and orgasm.34,35 It is therefore perhaps unsurprising that sexual dysfunction is observable in 30%–80% of patients after they begin taking SSRIs.23,24,27,35,36 Again unsurprisingly, sexual dysfunction seems to be one of the main reasons for discontinuing the intake of SSRIs,37–39 a pattern observed in up to 90% of patients treated with SSRIs.40 Therefore, it is important to identify strategies that can alleviate SSRI-I SD.25,37,38,40 SSRI-I SD is regarded as such a serious disability prob￾ably because for humans, sexual activity and sexual intimacy may serve at least four distinct goals: 1) exploring one’s partner’s values; 2) reproduction; 3) pair-bonding and pair stabilization;41 and 4) joy 42–45 or quality of life.25,45 Among humans, sexual activity within couples usually signifies exclusivity, intimacy, and bond-reinforcing behavior.41 The sexual activity and sexual intercourse in heterosexual couples can occur under many different conditions: 1) before and after the female’s fertile phase (ovulation); 2) during preg￾nancy; and 3) in females, during post-menopausal stage, thus indicating that, for heterosexual couples, sexual intercourse must serve needs beyond mere reproduction. Further, unlike with bonobos and chimpanzees, who belong to the two species closest to humans and who are sexually active in the presence and sight of other group members, humans, in all cultures and regardless of sexual orientation, engage in sexual relations in private and beyond the view of others; these practices further reinforce exclusive intimacy between partners. Given the exclusivity of sexual activity and its importance to bonding and bonding quality, it is not surpris￾ing its impairment is regarded as distressing and disturbing both for the individual and for couple-related quality of life. This holds particularly true for patients suffering from MDD, even during the recovery phase. For example, Clayton et al25 reported that among patients suffering from MDD, the use of SSRIs was associated with sexual dysfunction and hence had further implications for compliance and distress for the patient and her or his sexual satisfaction. Overall, the evidence strongly supports the view that among humans, sexual activity has importance beyond mere

Dovepress Rosa damascena oil for male SSRl-induced sexual dysfunction reproduction,that it is seriously impaired during MDD.and it to destinations all around the world.3354 The extract has that the most disturbing side effect of SSRI treatment is also been found to have medicinal properties.It has shown SSRI-I SD. antimicrobial activity.It also has been reported to protect Recommended treatments ofSSRI-I SD involve commer- neurons against amyloid B toxicity,a major pathological cially available medications such as sildenafil (Viagra),467 component of Alzheimer's disease,and to protect rats against tadalafil (Cialis"),47 mianserin,48 and bupropion.4 Further, seizures.s-ss The active components of R.damascena are not several case reports have been published that focus on the known.R.damascena oil is composed of a large number of use of antidotes such as cyproheptadine and on augment- volatile organic compounds including various terpenes such ing agents including gingko biloba,sildenafil,tadalafil,as citronellol,heneicosane,and disiloxane.The marc,mate- amantadine,bethanechol,bromocriptine,bupropion,dex- rial left after rose oil is extracted,has significant polyphenol troamphetamine,granisetron,loratadine,methylphenidate, content,including quercetin,myricetin,kaempferol,and mianserin,mirtazapine,nefazodone,neostigmine,pemo- gallic acid,though the predominant molecules have been sug- line,pramipexole,ropinirole,trazodone,vardenafil,and gested to be glycosides of quercetin and kaempferol.40 With yohimbine.(Extensive reviews are provided by Segraves regard to the effects of R.damescena on sexual dysfunction, and Balon3o and by Balon alone).35 However,Nurnberg40 we currently lack evidence based on double-blind,random- concludes that: ized,and placebo-controlled clinical trials.Accordingly,the aim of this study was to test the hypothesis that the adjuvant ....despite several thousand published reports on treat- administration of R.damascena oil has a favorable effect ment modalities based on heuristic post hoc hypotheses of on sexual dysfunction among male patients suffering from central serotonin inhibition and those involving agonist, MDD and SSRI-I SD. antagonist,partial agonist,switching,augmentation,and The following three hypotheses were formulated.First, waiting management approaches,no evidence-based data following Boskabady et alsI we anticipated the adjuvant are available to support those treatment modalities,leaving administration of R.damascena oil would improve sexual patients exposed to random pharmacology dysfunction among male patients suffering from MDD Moreover,to the best of our knowledge,there is no US and SSRI-I SD.Second,we expected that the adminis- Food and Drug Administration(FDA)-approved pharmaco- tration of R.damascena would alleviate symptoms of logical treatment for SSRI-I SD,and there is a shortage of depression.Third,we expected that the improvements in randomized,placebo-controlled,and double-blind clinical symptoms of depression and of sexual dysfunction would trials of potential treatments.To address the latter issue, be associated. the aim of the present study was to conduct a double-blind, randomized,and placebo-controlled clinical trial examining Method the effect of R.damascena oil,a herbal agent,on SSRI-I SD Study design among male patients suffering from MDD. The study entailed an 8-week,randomized,double-blind, In the context of more traditional treatments based on placebo-controlled clinical trial.The entire study was phytopharmaca,the oil of R.damascena is particularly wor- approved by the local ethics committee and conducted thy of attention because within the long history of Persian in accordance with the ethical standards laid down in medicine,R.damascena has been well known for its positive the Declaration of Helsinki(trial registration number: effects on mood,on a broad range of illnesses and diseases, IRCT2013100814333N10;http://www.irct.ir.). and,most importantly,on sexual dysfunction.5!R.dama- scena is a hybrid rose species predominantly grown in Iran, Procedure and sample Turkey,and Bulgaria to produce rose oil and rose water to Figure 1 shows the Consolidated Standards of Reporting be used in perfume and in the cosmetic and food industries.Trials flowchart for patient sampling.Male patients who The cultivation and consumption of R.damascena in Iran has were diagnosed with MDD,treated with SSRIs,and com- a long history,and Iran is one of its origins.32 It is believed plained about sexual dysfunction after commencement of that the crude distillation of roses for the oil originated in the SSRI regimen were recruited between October 2013 Persia in the late 7th century AD and spread to the provinces and June 2014 at the Outpatients Clinic of Farabi Hospital, of the Ottoman Empire in the 14th century.Iran was the Kermanshah University of Medical Sciences in Kermanshah, main producer ofrose oil until the 16th century and exported Iran.So that only patients suffering from MDD and Neuropsychiatric Disease and Treatment 2015:II submit your 627 Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 627 Rosa damascena oil for male SSRI-induced sexual dysfunction reproduction, that it is seriously impaired during MDD, and that the most disturbing side effect of SSRI treatment is SSRI-I SD. Recommended treatments of SSRI-I SD involve commer￾cially available medications such as sildenafil (Viagra®),46,47 tadalafil (Cialis®),47 mianserin,48 and bupropion.49 Further, several case reports have been published that focus on the use of antidotes such as cyproheptadine and on augment￾ing agents including gingko biloba, sildenafil, tadalafil, amantadine, bethanechol, bromocriptine, bupropion, dex￾troamphetamine, granisetron, loratadine, methylphenidate, mianserin, mirtazapine, nefazodone, neostigmine, pemo￾line, pramipexole, ropinirole, trazodone, vardenafil, and yohimbine. (Extensive reviews are provided by Segraves and Balon50 and by Balon alone).35 However, Nurnberg40 concludes that: ….despite several thousand published reports on treat￾ment modalities based on heuristic post hoc hypotheses of central serotonin inhibition and those involving agonist, antagonist, partial agonist, switching, augmentation, and waiting management approaches, no evidence-based data are available to support those treatment modalities, leaving patients exposed to random pharmacology. Moreover, to the best of our knowledge, there is no US Food and Drug Administration (FDA)-approved pharmaco￾logical treatment for SSRI-I SD, and there is a shortage of randomized, placebo-controlled, and double-blind clinical trials of potential treatments. To address the latter issue, the aim of the present study was to conduct a double-blind, randomized, and placebo-controlled clinical trial examining the effect of R. damascena oil, a herbal agent, on SSRI-I SD among male patients suffering from MDD. In the context of more traditional treatments based on phytopharmaca, the oil of R. damascena is particularly wor￾thy of attention because within the long history of Persian medicine, R. damascena has been well known for its positive effects on mood, on a broad range of illnesses and diseases, and, most importantly, on sexual dysfunction.51 R. dama￾scena is a hybrid rose species predominantly grown in Iran, Turkey, and Bulgaria to produce rose oil and rose water to be used in perfume and in the cosmetic and food industries. The cultivation and consumption of R. damascena in Iran has a long history, and Iran is one of its origins.52 It is believed that the crude distillation of roses for the oil originated in Persia in the late 7th century AD and spread to the provinces of the Ottoman Empire in the 14th century. Iran was the main producer of rose oil until the 16th century and exported it to destinations all around the world.53,54 The extract has also been found to have medicinal properties. It has shown antimicrobial activity. It also has been reported to protect neurons against amyloid β toxicity, a major pathological component of Alzheimer’s disease, and to protect rats against seizures.55–58 The active components of R. damascena are not known. R. damascena oil is composed of a large number of volatile organic compounds including various terpenes such as citronellol, heneicosane, and disiloxane.59 The marc, mate￾rial left after rose oil is extracted, has significant polyphenol content, including quercetin, myricetin, kaempferol, and gallic acid, though the predominant molecules have been sug￾gested to be glycosides of quercetin and kaempferol.60 With regard to the effects of R. damescena on sexual dysfunction, we currently lack evidence based on double-blind, random￾ized, and placebo-controlled clinical trials. Accordingly, the aim of this study was to test the hypothesis that the adjuvant administration of R. damascena oil has a favorable effect on sexual dysfunction among male patients suffering from MDD and SSRI-I SD. The following three hypotheses were formulated. First, following Boskabady et al51 we anticipated the adjuvant administration of R. damascena oil would improve sexual dysfunction among male patients suffering from MDD and SSRI-I SD. Second, we expected that the adminis￾tration of R. damascena would alleviate symptoms of depression. Third, we expected that the improvements in symptoms of depression and of sexual dysfunction would be associated. Method Study design The study entailed an 8-week, randomized, double-blind, placebo-controlled clinical trial. The entire study was approved by the local ethics committee and conducted in accordance with the ethical standards laid down in the Declaration of Helsinki (trial registration number: IRCT2013100814333N10; http://www.irct.ir.). Procedure and sample Figure 1 shows the Consolidated Standards of Reporting Trials flowchart for patient sampling. Male patients who were diagnosed with MDD, treated with SSRIs, and com￾plained about sexual dysfunction after commencement of the SSRI regimen were recruited between October 2013 and June 2014 at the Outpatients Clinic of Farabi Hospital, Kermanshah University of Medical Sciences in Kermanshah, Iran. So that only patients suffering from MDD and

Farnia et al Dovepress Assessed for eligibility(n=127) Excluded (n=59) Not meeting inclusion criteria(n=31) Refused to participate before further assessments(n=12) Excluded according exclusion criteria(n=16) Randomized(n=68) Rosa damascena Placebo group (n=33) group (n=35) Received allocated Received allocated intervention(n=33) intervention(n=35) 号 Erratic use of medication Erratic use of placebo and ollO and discontinued intervention discontinued intervention before 8 weeks(n=5) before 8 weeks(n=3) Analyzed(n=30) Analyzed(n=30) Figure I CONSORT diagram showing the flow of participants through each stage. Abbreviations:n,number of subjects;CONSORT.Consolidated Standards of Reporting Trials experiencing sexual dysfunction after starting the SSRI A male patient was included in the study if the fol- regimen were included,trained professional psychiatrists lowing criteria were met:1)he was suffering from an performed interviews based on the structured clinical inter- MDD that was diagnosed by a psychiatrist and was view for psychiatric disorders(Mini International Neurop- based on the DSM-5 criteria;62 2)he was suffering from sychiatric Interview).51 Eligible patients(number [n]=127) SSRI-I SD according to the DSM-5;3)he scored at least were fully informed about the study aims and procedure 19 points or more on the self-rated depressive symptoms and about the confidential nature of data selection and data on the Beck Depression Inventory(BDI)and could thus be handling,and all of the patients gave their written informed diagnosed with moderate major depression;4)he scored consent.At that time,all eligible patients were in an acute 2 points or less for self-rated sexual dysfunction,as assessed depressive state according to the Diagnostic and Statistical via the Brief Sexual Function Inventory(BSFD);63 5)he had Manual of Mental Disorders,fifth edition (DSM-5)criteria.2 continuous pharmacological treatment with SSRIs for at Prior to being enrolled in the present study,patients had been least 6 weeks prior to entering the study;and 6)he signed a treated with and stabilized on an SSRI(standard medica- written informed consent form. tion)for at least 6 weeks.The treatment regimen remained Subjects were excluded if they met any of these criteria: unaltered throughout the 8-week duration of the study. 1)the subject did not meet the inclusion criteria as described 628 Neuropsychiatric Disease and Treatment 2015:II Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 628 Farnia et al ([FOXGHGQ  1RWPHHWLQJLQFOXVLRQFULWHULDQ  5HIXVHGWRSDUWLFLSDWHEHIRUH IXUWKHUDVVHVVPHQWVQ  ([FOXGHGDFFRUGLQJH[FOXVLRQ FULWHULDQ  5DQGRPL]HGQ  5RVDGDPDVFHQD JURXSQ  5HFHLYHGDOORFDWHG LQWHUYHQWLRQQ  $OORFDWLRQ $VVHVVHGIRUHOLJLELOLW\Q  3ODFHERJURXSQ  5HFHLYHGDOORFDWHG LQWHUYHQWLRQQ  )ROORZXS (QUROOPHQW (UUDWLFXVHRIPHGLFDWLRQ DQGGLVFRQWLQXHGLQWHUYHQWLRQ EHIRUHZHHNVQ  (UUDWLFXVHRISODFHER DQG GLVFRQWLQXHGLQWHUYHQWLRQ EHIRUHZHHNVQ  $QDO\VLV $QDO\]HGQ  $QDO\]HGQ  Figure 1 CONSORT diagram showing the flow of participants through each stage. Abbreviations: n, number of subjects; CONSORT, Consolidated Standards of Reporting Trials. experiencing sexual dysfunction after starting the SSRI regimen were included, trained professional psychiatrists performed interviews based on the structured clinical inter￾view for psychiatric disorders (Mini International Neurop￾sychiatric Interview).61 Eligible patients (number [n]=127) were fully informed about the study aims and procedure and about the confidential nature of data selection and data handling, and all of the patients gave their written informed consent. At that time, all eligible patients were in an acute depressive state according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria.62 Prior to being enrolled in the present study, patients had been treated with and stabilized on an SSRI (standard medica￾tion) for at least 6 weeks. The treatment regimen remained unaltered throughout the 8-week duration of the study. A male patient was included in the study if the fol￾lowing criteria were met: 1) he was suffering from an MDD that was diagnosed by a psychiatrist and was based on the DSM-5 criteria;62 2) he was suffering from SSRI-I SD according to the DSM-5; 3) he scored at least 19 points or more on the self-rated depressive symptoms on the Beck Depression Inventory (BDI) and could thus be diagnosed with moderate major depression; 4) he scored 2 points or less for self-rated sexual dysfunction, as assessed via the Brief Sexual Function Inventory (BSFI);63 5) he had continuous pharmacological treatment with SSRIs for at least 6 weeks prior to entering the study; and 6) he signed a written informed consent form. Subjects were excluded if they met any of these criteria: 1) the subject did not meet the inclusion criteria as described

Dovepress Rosa damascena oil for male SSRl-induced sexual dysfunction previously;2)he withdrew from the study;3)he was taking Medication any medication or drug that may affect sexual function;4)he Patients took their standard SSRI-medications (duloxetine. had any underlying medical or psychiatric disorder(except escitalopram,venlafaxine,or sertraline).Dosages were indi- MDD)that may interfere with sexual function;or 5)he vidually adapted to patients and kept constant for 6 weeks prior reported side effects(changes in physical and psychological to the start of the study in order to achieve treatment efficacy. well-being)related to adjuvant medication(intake of either Next,patients took either verum or placebo in the morn- the verum or the placebo).No side effects were reported at ing.The verum dosage was 2 mL/day and contained 17 mg any time during the study. Citronellol of essential oil of R.damascena(drops),whereas Ofthe 127 patients screened,68 were randomly assigned the placebo consisted of 2 mL/day of an oil-water solution either to the verum group or to the placebo group.Random-with an identical scent.The verum and placebo flacons were ization occurred as follows:35 blue(for verum)and 35 red identical in shape,weight,look,and,once opened,scent. (for placebo)chips were put in a ballot box and stirred; (The verum was based on at least 5.8 mg citronellol patients drew a chip and were then assigned to the corre- in each mL of product;the active ingredients are citro- sponding group.Neither the patients nor the hospital staff nellol,geraniol,nerol,linalool,and phenyl ethyl alcohol. responsible for the randomization knew the group to which Additional components include linalool,saturated fatty any of the subjects had been assigned.Furthermore,none alcohols beta-phenyl-ethyl alcohol,farnesol,terpinene-1- of the personnel involved in the study knew the group to ol-4,acetates of the indicated alcohols,free acids,aldehydes which any of the patients had been assigned.The principal [fatty and aromatic],geranial,neral,ketones,phenols,phe- investigator,Vahid Farnia,was not involved in performing nol esters,hydrocarbons,rose oxide,and stearoptene.The the study verum was manufactured by Barij Essence Pharmaceutical At baseline,35 patients were assigned to the verum group Company in Kashan,Iran). and 33 were assigned to the placebo group.The two groups did not differ with respect to age(verum:mean age=32.45 years, Assessing SSRl-induced sexual dysfunction standard deviation =5.68 years;placebo:mean age To assess SSRI-I SD,after the thorough psychiatric inter- =34.02 years,standard deviation=6.45 years;t(66)=1.34,view,psychiatrists also explored the sexual dysfunctions of P=0.54),symptom severity,or sexual dysfunction each patient before he started the treatment with an SSRI, (Table 1).At follow-up,five patients dropped out of the at least 6 weeks before each patient entered the study,and verum group,and three dropped out of the placebo group. sexual dysfunction during the study.An SSRI-I SD was However,statistical computation was performed with the diagnosed in accordance with the DSM-5;3 if all other fac- intention-to-treat algorithm and not with the per-protocol tors were equal,sexual dysfunction emerged with the start algorithm. of SSRI intake. Table I Descriptive overview of the sexual dysfunction and depressive symptoms scores each group(verum versus placebo)for each assessment time (baseline,week 4,and week 8) Assessment times Baseline Week 4 Week 8 Group Verum Placebo Verum Placebo Verum Placebo N 35 33 35 33 35 33 M±SD M±SD M±SD M±SD M±SD M±SD Sexual drive 1.8±0.84 1.84±0.63 2.07±0.81 188±0.71 2.43±0.98 2.03±0.80 Erections 1.78±0.76 1.94±0.69 1.77±0.72 1.82±0.74 2.49±1.09 2.05±0.81 Ejaculations 1.89±0.79 1.92±0.68 2.01±0.78 188±0.72 2.71±1.10 2.2010.92 Problem assessment 1.79±0.99 1.84牡0.63 1.90±0.84 1.86±0.71 2.68±1.07 2.15±0.90 Overall satisfaction 1.71±0.89 1.88±0.64 2.14±0.91 1.90±0.68 2.68±1.11 2.33±1.05 Mean score 1.81±0.78 1.89±0.63 1.98±0.73 1.87±0.68 2.58±1.01 2.16±0.87 Beck Depression Inventory 18.93±5.48 18.45±5.43 16.03±475 18.33+5.30 Notes:The verum is from Rosa damascena.Week 8marks the end of the study. Abbreviations:N,number of subjects:M.mean:SD.standard deviation. Neuropsychiatric Disease and Treatment 2015:1I ubmit yo 629 Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 629 Rosa damascena oil for male SSRI-induced sexual dysfunction previously; 2) he withdrew from the study; 3) he was taking any medication or drug that may affect sexual function; 4) he had any underlying medical or psychiatric disorder (except MDD) that may interfere with sexual function; or 5) he reported side effects (changes in physical and psychological well-being) related to adjuvant medication (intake of either the verum or the placebo). No side effects were reported at any time during the study. Of the 127 patients screened, 68 were randomly assigned either to the verum group or to the placebo group. Random￾ization occurred as follows: 35 blue (for verum) and 35 red (for placebo) chips were put in a ballot box and stirred; patients drew a chip and were then assigned to the corre￾sponding group. Neither the patients nor the hospital staff responsible for the randomization knew the group to which any of the subjects had been assigned. Furthermore, none of the personnel involved in the study knew the group to which any of the patients had been assigned. The principal investigator, Vahid Farnia, was not involved in performing the study. At baseline, 35 patients were assigned to the verum group and 33 were assigned to the placebo group. The two groups did not differ with respect to age (verum: mean age =32.45 years, standard deviation =5.68 years; placebo: mean age =34.02 years, standard deviation =6.45 years; t(66)=1.34, P=0.54), symptom severity, or sexual dysfunction (Table 1). At follow-up, five patients dropped out of the verum group, and three dropped out of the placebo group. However, statistical computation was performed with the intention-to-treat algorithm and not with the per-protocol algorithm. Medication Patients took their standard SSRI-medications (duloxetine, escitalopram, venlafaxine, or sertraline). Dosages were indi￾vidually adapted to patients and kept constant for 6 weeks prior to the start of the study in order to achieve treatment efficacy. Next, patients took either verum or placebo in the morn￾ing. The verum dosage was 2 mL/day and contained 17 mg Citronellol of essential oil of R. damascena (drops), whereas the placebo consisted of 2 mL/day of an oil–water solution with an identical scent. The verum and placebo flacons were identical in shape, weight, look, and, once opened, scent. (The verum was based on at least 5.8 mg citronellol in each mL of product; the active ingredients are citro￾nellol, geraniol, nerol, linalool, and phenyl ethyl alcohol. Additional components include linalool, saturated fatty alcohols beta-phenyl-ethyl alcohol, farnesol, terpinene-1- ol-4, acetates of the indicated alcohols, free acids, aldehydes [fatty and aromatic], geranial, neral, ketones, phenols, phe￾nol esters, hydrocarbons, rose oxide, and stearoptene. The verum was manufactured by Barij Essence Pharmaceutical Company in Kashan, Iran). Assessing SSRI-induced sexual dysfunction To assess SSRI-I SD, after the thorough psychiatric inter￾view, psychiatrists also explored the sexual dysfunctions of each patient before he started the treatment with an SSRI, at least 6 weeks before each patient entered the study, and sexual dysfunction during the study. An SSRI-I SD was diagnosed in accordance with the DSM-5; 63 if all other fac￾tors were equal, sexual dysfunction emerged with the start of SSRI intake. Table 1 Descriptive overview of the sexual dysfunction and depressive symptoms scores each group (verum versus placebo) for each assessment time (baseline, week 4, and week 8) Assessment times Baseline Week 4 Week 8 Group Verum Placebo Verum Placebo Verum Placebo N 35 33 35 33 35 33 M ± SD M ± SD M ± SD M ± SD M ± SD M ± SD Sexual drive 1.8±0.84 1.84±0.63 2.07±0.81 1.88±0.71 2.43±0.98 2.03±0.80 Erections 1.78±0.76 1.94±0.69 1.77±0.72 1.82±0.74 2.49±1.09 2.05±0.81 Ejaculations 1.89±0.79 1.92±0.68 2.01±0.78 1.88±0.72 2.71±1.10 2.20±0.92 Problem assessment 1.79±0.99 1.84±0.63 1.90±0.84 1.86±0.71 2.68±1.07 2.15±0.90 Overall satisfaction 1.71±0.89 1.88±0.64 2.14±0.91 1.90±0.68 2.68±1.11 2.33±1.05 Mean score 1.81±0.78 1.89±0.63 1.98±0.73 1.87±0.68 2.58±1.01 2.16±0.87 Beck Depression Inventory 18.93±5.48 18.45±5.43 – – 16.03±4.75 18.33±5.30 Notes: The verum is from Rosa damascena. Week 8 marks the end of the study. Abbreviations: N, number of subjects; M, mean; SD, standard deviation

Farnia et al Dovepress Instruments Greenhouse-Geisser epsilon value(E).For ANOVAs,effect Self-assessment of depressive symptoms by using the BDI sizes are indicated with the partial eta squared (n2),with Patients completed the BDI,64 which a self-report of symp- 0.059≥n≥0.01 indicating small(s),0.139≥n2≥0.06 toms of depression.The questionnaire consists of 21 items indicating medium(M),and n2=0.14 indicating large (L) and covers such areas as depressive mood,loss of appetite, effect sizes.All computations were performed as intention- sleep disorders,and suicidal thoughts.Answers are given to-treat and the last observation carried forward. on 4-point Likert scales with the anchor points 0(for"as The nominal alpha-level was set at 0.05;post hoc analy- always”or“no change')and3(for“not able anymore” ses were performed with Bonferroni-Holm corrections of or "dramatic change")and with higher scores reflecting P-values for multiple testing.Statistical analyses were per- greater severity of depressive symptoms(Cronbach's formed with SPSS*20.0(IBM Corporation,Armonk,NY, alpha =0.89). USA)for Apple MacIntosh". Self-assessment of sexual dysfunction by using the BSFI Results The BSFI63 contains eleven questions that cover five domains Sexual dysfunction over time and of sexual function:1)sexual drive (two items);2)erectile between verum and placebo groups function (three items);3)ejaculatory function (two items): Tables I and 2 show the descriptive and statistical overview 4)sexual problem assessment (three items);and 5)sexual of sexual function levels separately by assessment time(base- satisfaction(one item).Answers are given on a 5-point Lik- line,week 4,and 8 weeks later [at the end of the study])and ert scale with scores ranging from 0(none,big problem,or group (verum versus placebo). no activity)to 4(always,no problem,or high activity)and Sexual function improved significantly over time.Post with lower mean scores reflect greater sexual dysfunction hoc analyses with Bonferroni-Holm corrections for P-values (Cronbach's alpha =0.91). showed that sexual dysfunction reduced from week 4 to week 8.All effect sizes were large.No statistically significant Statistical analysis differences between the groups were observed. Preliminary calculations Significant time x group interactions were observed for To detect possible confounders,Spearman's correlations all sexual function variables.Effect sizes were large.Post were computed between sociodemographic data (age,edu- hoc analyses with Bonferroni-Holm corrections for P-values cation,civil status,medication intake,number of children) showed that sexual dysfunction was lower in the verum than and indices of sexual dysfunction and depressive symptoms. in the placebo group at week 8.Figure 2 shows the mean All correlation coefficients were between-0.05 and 0.15 values for the two groups over the three time points. (Ps >0.56);accordingly,sociodemographic data were not introduced as possible confounders. Depressive symptoms Next,a series of Pearson's correlations was performed Patients rated their depressive symptoms via the BDI at between dimensions of sexual dysfunction and depres- baseline and at the end of the study (Tables 1 and 2 and sive symptoms.Further,a series of analyses of variances Figure 3).Depressive symptoms declined over time;the (ANOVAs)for repeated measures was performed with the significant time x group interaction showed that depressive factors time (baseline,4 weeks,and 8 weeks)and group symptoms declined more in the verum group than in the (verum versus placebo),and with sexual dysfunction areas placebo group. (sexual drive,erections,ejaculations,problem assessment, overall satisfaction,and overall mean score)as dependent Correlations between sexual dysfunction variables.Additionally,another ANOVA was computed and symptoms of depression with the factors time(baseline,8 weeks)and group(verum Correlating symptoms of depression at baseline and after versus placebo),with the dependent variable BDI score,and 8 weeks (the end of the study)with sexual dysfunction with Bonferroni-Holm corrections for P-values.Because of showed that symptoms of depression and sexual dysfunction deviations from sphericity,ANOVAs for repeated measures were unrelated (allrs0.41).When correlations (for the factor time with three values)were performed using were calculated separately for the verum and placebo group, Greenhouse-Geisser corrected degrees of freedom,although the following pattern of results was observed:for the verum the original degrees of freedom are reported with the relevant group,again,symptoms of depression and sexual function 630 submit your manus Neuropsychiatric Disease and Treatment 2015:II Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 630 Farnia et al Instruments Self-assessment of depressive symptoms by using the BDI Patients completed the BDI,64 which a self-report of symp￾toms of depression. The questionnaire consists of 21 items and covers such areas as depressive mood, loss of appetite, sleep disorders, and suicidal thoughts. Answers are given on 4-point Likert scales with the anchor points 0 (for “as always” or “no change”) and 3 (for “not able anymore” or “dramatic change”) and with higher scores reflecting greater severity of depressive symptoms (Cronbach’s alpha =0.89). Self-assessment of sexual dysfunction by using the BSFI The BSFI63 contains eleven questions that cover five domains of sexual function: 1) sexual drive (two items); 2) erectile function (three items); 3) ejaculatory function (two items); 4) sexual problem assessment (three items); and 5) sexual satisfaction (one item). Answers are given on a 5-point Lik￾ert scale with scores ranging from 0 (none, big problem, or no activity) to 4 (always, no problem, or high activity) and with lower mean scores reflect greater sexual dysfunction (Cronbach’s alpha =0.91). Statistical analysis Preliminary calculations To detect possible confounders, Spearman’s correlations were computed between sociodemographic data (age, edu￾cation, civil status, medication intake, number of children) and indices of sexual dysfunction and depressive symptoms. All correlation coefficients were between -0.05 and 0.15 (Ps .0.56); accordingly, sociodemographic data were not introduced as possible confounders. Next, a series of Pearson’s correlations was performed between dimensions of sexual dysfunction and depres￾sive symptoms. Further, a series of analyses of variances (ANOVAs) for repeated measures was performed with the factors time (baseline, 4 weeks, and 8 weeks) and group (verum versus placebo), and with sexual dysfunction areas (sexual drive, erections, ejaculations, problem assessment, overall satisfaction, and overall mean score) as dependent variables. Additionally, another ANOVA was computed with the factors time (baseline, 8 weeks) and group (verum versus placebo), with the dependent variable BDI score, and with Bonferroni–Holm corrections for P-values. Because of deviations from sphericity, ANOVAs for repeated measures (for the factor time with three values) were performed using Greenhouse–Geisser corrected degrees of freedom, although the original degrees of freedom are reported with the relevant Greenhouse–Geisser epsilon value (ε). For ANOVAs, effect sizes are indicated with the partial eta squared (η2 ), with 0.059 $ η2 $0.01 indicating small (S), 0.139 $ η2 $0.06 indicating medium (M), and η2 $0.14 indicating large (L) effect sizes. All computations were performed as intention￾to-treat and the last observation carried forward. The nominal alpha-level was set at 0.05; post hoc analy￾ses were performed with Bonferroni–Holm corrections of P-values for multiple testing. Statistical analyses were per￾formed with SPSS® 20.0 (IBM Corporation, Armonk, NY, USA) for Apple MacIntosh®. Results Sexual dysfunction over time and between verum and placebo groups Tables 1 and 2 show the descriptive and statistical overview of sexual function levels separately by assessment time (base￾line, week 4, and 8 weeks later [at the end of the study]) and group (verum versus placebo). Sexual function improved significantly over time. Post hoc analyses with Bonferroni–Holm corrections for P-values showed that sexual dysfunction reduced from week 4 to week 8. All effect sizes were large. No statistically significant differences between the groups were observed. Significant time × group interactions were observed for all sexual function variables. Effect sizes were large. Post hoc analyses with Bonferroni–Holm corrections for P-values showed that sexual dysfunction was lower in the verum than in the placebo group at week 8. Figure 2 shows the mean values for the two groups over the three time points. Depressive symptoms Patients rated their depressive symptoms via the BDI at baseline and at the end of the study (Tables 1 and 2 and Figure 3). Depressive symptoms declined over time; the significant time × group interaction showed that depressive symptoms declined more in the verum group than in the placebo group. Correlations between sexual dysfunction and symptoms of depression Correlating symptoms of depression at baseline and after 8 weeks (the end of the study) with sexual dysfunction showed that symptoms of depression and sexual dysfunction were unrelated (all rs,0.11, ps.0.41). When correlations were calculated separately for the verum and placebo group, the following pattern of results was observed: for the verum group, again, symptoms of depression and sexual function

Dovepress Rosa damascena oil for male SSRI-induced sexual dysfunction Table 2 Overview of the inferential statistics for the factors time(baseline,week 4,week 8)and group (verum versus placebo)with sexual function as the dependent variable Time Group Time x group Greenhouse- Post hoc analyses interaction Geisser epsilon Degrees of freedom (2,132) (,66) (2,132) Time Group Fn2(EF) Fn2(EF) Fn2(EF) Sexual drive 13.65*0.171() 1230.018() 3.98*0.056(M） 0.827 W8>W4.BL V>PL at W8 Erections 23.04*0.259(L) 0.190.003(S) 9.12*0.121(M 0.793 W8>W4.BL V>PL at W8 Ejaculations 30.88*0.319()） 1.I10.017(S 5.91*0.078(M 0.662 W8>W4.BL V>PL at W8 Problem assessment 30.72*0.319(L) 0.960.008(S) 5.56*0.082(M 0.736 W8>W4.BL V>PL at W8 Overall satisfaction 30.12*0.354(L) 0.900.012(S) 4.59*0.065(M 0.686 W8>W4.BL V>PL at W8 Mean score 34.43*0.343(L) 0.720.010(⑤) 723钟0.100(M 0.659 W8>W4.BL V>PL at W8 Degrees of freedom (0,66) (1,66) (1,66) Fn2(EF) Fn2(EF) Fn2(EF) Beck depression inventory 11.82**0.182 (L) 0.770.001(S 9.07*0.131(M 1.00 Notes:*=PW4,BL"indicates that all values at week 8 were statistically higher than the values at week 4 and at baseline."V>PL at W8"indicates that at week 8,values of the verum group were statistically higher than the values of the placebo group. Abbreviations:EF,effect size:S.small effect size;M,medium effect size;L.large effect size;W8,week 8:W4.week 4;BL baseline;V.verum;PL,placebo were unrelated (all rs0.38);for the placebo placebo did.Symptoms of depression decreased in parallel, group,more severe symptoms of depression at baseline pre- but not linearly.These results confirm the positive effect of dicted greater sexual dysfunction at baseline,and after 4 and R.damascena oil on SSRI-I SD in a double-blind,random- 8 weeks(rs>0.35,ps0.38, Three hypotheses were formulated.Our first hypothesis ps<0.05),but not with sexual dysfunction at baseline. was that the administration of R.damascena oil would improve sexual dysfunction more than a placebo would,and Discussion this theory was fully supported.Accordingly,the present The key findings of the present study are that among male study is a contribution to the current literature because,to patients suffering from both MDD and SSRI-ISD while being the best of our knowledge,for the first time the success of treated with an SSRI standard medication,adjuvant admin- an agent in the treatment of an SSRI-I SD in male patients istration of R.damascena oil improved sexual dysfunction suffering from MDD was proven in a double-blind,random- after 8 weeks more than the adjuvant administration of the ized,and placebo-controlled clinical trial. 4.0 30 35 ◆=Verum ■Placebo ◆=Verum-d-Placebo 25 25 20 2.0 15 品 10 1.0 0.5 5 0.0- Baseline Week 4 Week 8 0 Baseline Week 8(end of study) (end of study) Time points Time points Figure 3 Comparison of BDI scores between verum and placebo groups. Figure 2 Comparison of sexual function between verum and placebo groups Notes:Over time,symptoms of depression(BDI scores)decreased significantly Notes:Over time,sexual dysfunction improved significantly more in the verum more in the verum(Rosa damascena extract)group than in the placebo group.Points (Rosa damascena oil)group than in the placebo group.Points are means,and bars are means,and bars are standard deviations. are standard errors. Abbreviation:BDI,Beck Depression Inventory. Neuropsychiatric Disease and Treatment 2015:1I 631 Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 631 Rosa damascena oil for male SSRI-induced sexual dysfunction were unrelated (all rs,0.13, ps.0.38); for the placebo group, more severe symptoms of depression at baseline pre￾dicted greater sexual dysfunction at baseline, and after 4 and 8 weeks (rs.0.35, ps,0.05). A greater severity of depression symptoms after 8 weeks was associated with greater sexual dysfunction after weeks 4 and 8 of the study (rs.0.38, ps,0.05), but not with sexual dysfunction at baseline. Discussion The key findings of the present study are that among male patients suffering from both MDD and SSRI-I SD while being treated with an SSRI standard medication, adjuvant admin￾istration of R. damascena oil improved sexual dysfunction after 8 weeks more than the adjuvant administration of the placebo did. Symptoms of depression decreased in parallel, but not linearly. These results confirm the positive effect of R. damascena oil on SSRI-I SD in a double-blind, random￾ized, and placebo-controlled clinical trial and provide an important contribution to the literature on this condition. Three hypotheses were formulated. Our first hypothesis was that the administration of R. damascena oil would improve sexual dysfunction more than a placebo would, and this theory was fully supported. Accordingly, the present study is a contribution to the current literature because, to the best of our knowledge, for the first time the success of an agent in the treatment of an SSRI-I SD in male patients suffering from MDD was proven in a double-blind, random￾ized, and placebo-controlled clinical trial. Table 2 Overview of the inferential statistics for the factors time (baseline, week 4, week 8) and group (verum versus placebo) with sexual function as the dependent variable Time Group Time × group interaction Greenhouse– Geisser epsilon Post hoc analyses Degrees of freedom (2, 132) (1, 66) (2, 132) Time Group F η2 (EF) F η2 (EF) F η2 (EF) Sexual drive 13.65*** 0.171 (L) 1.23 0.018 (S) 3.98* 0.056 (M) 0.827 W8 . W4, BL V . PL at W8 Erections 23.04*** 0.259 (L) 0.19 0.003 (S) 9.12** 0.121 (M) 0.793 W8 . W4, BL V . PL at W8 Ejaculations 30.88*** 0.319 (L) 1.11 0.017 (S) 5.91** 0.078 (M) 0.662 W8 . W4, BL V . PL at W8 Problem assessment 30.72*** 0.319 (L) 0.96 0.008 (S) 5.56** 0.082 (M) 0.736 W8 . W4, BL V . PL at W8 Overall satisfaction 30.12*** 0.354 (L) 0.90 0.012 (S) 4.59* 0.065 (M) 0.686 W8 . W4, BL V . PL at W8 Mean score 34.43*** 0.343 (L) 0.72 0.010 (S) 7.23** 0.100 (M) 0.659 W8 . W4, BL V . PL at W8 Degrees of freedom (1, 66) (1, 66) (1, 66) F η2 (EF) F η2 (EF) F η2 (EF) Beck depression inventory 11.82** 0.182 (L) 0.77 0.001 (S) 9.07** 0.131 (M) 1.00 – – Notes: * = P,0.05; ** = P,0.01; *** = P,0.001. “W8 . W4, BL” indicates that all values at week 8 were statistically higher than the values at week 4 and at baseline. “V . PL at W8” indicates that at week 8, values of the verum group were statistically higher than the values of the placebo group. Abbreviations: EF, effect size; S, small effect size; M, medium effect size; L, large effect size; W8, week 8; W4, week 4; BL, baseline; V, verum; PL, placebo.          %DVHOLQH :HHN 7LPHSRLQWV 6H[XDOIXQFWLRQ :HHN HQGRIVWXG\ 9HUXP 3ODFHER Figure 2 Comparison of sexual function between verum and placebo groups. Notes: Over time, sexual dysfunction improved significantly more in the verum (Rosa damascena oil) group than in the placebo group. Points are means, and bars are standard errors.     %',VFRUHV 7LPHSRLQWV    %DVHOLQH :HHNHQGRIVWXG\ 9HUXP 3ODFHER Figure 3 Comparison of BDI scores between verum and placebo groups. Notes: Over time, symptoms of depression (BDI scores) decreased significantly more in the verum (Rosa damascena extract) group than in the placebo group. Points are means, and bars are standard deviations. Abbreviation: BDI, Beck Depression Inventory.

Farnia et al Dovepress Our second hypothesis was that symptoms of depression behavioral deficiencies,restore astrocytes and microglia. would improve with adjuvant administration of R.damascena and reduce serotonin metabolism in a 3-nitropropionic acid- oil,and this was also supported.Symptoms of depression induced rat model of Huntington's Disease.36 Last,Merzoug declined in both groups,but the decline was greater in the et als7 reported that quercetin mitigated Adriamycin-induced verum group(Tables 1 and 2 and Figure 3).Thus,we were anxiety-and depression-like behaviors,immune dysfunction, also able to show that R.damascena oil had an adjuvant and brain oxidative stress in rats. effect on symptoms of depression.However,the present With regard to the glycoside kaempferol,evidence from pattern of results expands on previous findingss!because animal studies has shown an antidepressant and modulating the results were based on a double-blind,randomized,and effect on brain-derived neurotrophic factor and B amyloid in placebo-controlled clinical trial. the neurons and hippocampus of double TgAD mice.68 Our third hypothesis was that improvements in depres- Overall,research on animal models suggest that both sive symptoms would occur in parallel to improvements in quercetin and kaempferol,two of the main agents of sexual dysfunction.This was not fully supported.Whereas R.damascena oil,seem to have beneficial influences on a pronounced improvement was observed in depressive symptoms of depression at the molecular level. symptoms in patients treated with adjuvant R.damascena Moreover,we also observe that explaining the occurrence oil,improvements of the same extent were not observed in and maintenance of MDD in terms of monoamine deficiency patients treated with the placebo.More importantly,a signifi- is just one of several putative pathways by which MDD might cant correlation between symptoms of depression and sexual be explained neurophysiologically and neuroendocrinologi- dysfunction was only observed in the placebo group.Thus, cally.In this regard,more recently efforts have been made whereas both symptoms of depression and sexual dysfunction to further investigate the roles of the neuropeptide brain- are closely associated,25 R.damascena oil seemed to have derived neurotrophic factor on MDD,10.69.70 on ketamine, different effects on symptoms of depression and on sexual and statins.2-75 With regard to statins,by using a mouse dysfunction in the verum group. model,Ludka et al'6 observed that after acute atorvastatin This last observation illustrates the primary limitation of treatment,the antidepressant effect seemed to be explained the present study:the data available do not shed any light on via the L-arginine-nitric oxide-cyclic guanosine mono- the neurophysiological mechanisms by which R.damascena phosphate pathway;atorvastatin seemed to inhibit NMDA oil has positive effects on symptoms of either depression (N-methyl-D-aspartatic acid)receptors and NO-cGMP(nitric or sexual dysfunction.Hence,the following proposals are oxide-cyclic guanosine monophosphate)synthesis,leading somewhat speculative;they are not strictly evidence-driven.to a down-regulation of excitatory processes.On a behav- With regard to improvements in sexual dysfunction,it is ioral level,this down-regulation seems to be reflected in a possible that agents of R.damascena oil have an antagonis-reduction of symptoms of depression.However,it remains tic effect on the stimulation of the postsynaptic 5-HT2 and unclear to what extent the new pathways explaining MDD 5-HT3 receptors30-32 and that these agents have an antago- neurophysiologically and neuroendocrinologically may nistic effect on the corticolimbic 5-HT receptors,which are help to better understand the influence of the agents of responsible for increasing sexual desire,ejaculation,and R.damascena oil on both symptoms of depression and sexual orgasm.Additionally,it is possible that the agents ofR. dysfunction. damascena agonistically increase the release of dopamine Despite the encouraging results,several limitations and norepinephrine in the substantia nigra,3132 as well as should be considered to prevent overgeneralization of the disinhibiting nitric oxide synthase.33 Further,R.damascena data.First,as we have noted,neither the precise effects of oil seems to have an antimicrobial effect,and has been the agents of R.damascena,nor their neurophysiological and reported to protect neurons against amyloid B toxicity,a neuroendocrinological influences on MDD and SSRI-I SD, major pathological component of Alzheimer's disease,and are well understood.Accordingly,the details of the underly- to protect rats against seizures.More specifically,it is sug- ing mechanisms remain,for the present,unresolved.Second, gested that the agent glycoside quercetin is also responsible participants were selected and recruited from one study center; for improving neuronal activity,probably by inducing the therefore,a systematic selection bias cannot be excluded.In expression of synaptic proteins synaptotagmin and post-this regard,third and most importantly,we cannot say whether synaptic density protein-95,at least in cultured rat cortical an identical pattern of results would also have been observed neurons.5 Likewise,quercetin has been shown to reduce with female patients.Fourth,the present pattern of results 632 submit your manuscrip Neuropsychiatric Disease and Treatment 2015:II Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 632 Farnia et al Our second hypothesis was that symptoms of depression would improve with adjuvant administration of R. damascena oil, and this was also supported. Symptoms of depression declined in both groups, but the decline was greater in the verum group (Tables 1 and 2 and Figure 3). Thus, we were also able to show that R. damascena oil had an adjuvant effect on symptoms of depression. However, the present pattern of results expands on previous findings51 because the results were based on a double-blind, randomized, and placebo-controlled clinical trial. Our third hypothesis was that improvements in depres￾sive symptoms would occur in parallel to improvements in sexual dysfunction. This was not fully supported. Whereas a pronounced improvement was observed in depressive symptoms in patients treated with adjuvant R. damascena oil, improvements of the same extent were not observed in patients treated with the placebo. More importantly, a signifi￾cant correlation between symptoms of depression and sexual dysfunction was only observed in the placebo group. Thus, whereas both symptoms of depression and sexual dysfunction are closely associated,25 R. damascena oil seemed to have different effects on symptoms of depression and on sexual dysfunction in the verum group. This last observation illustrates the primary limitation of the present study: the data available do not shed any light on the neurophysiological mechanisms by which R. damascena oil has positive effects on symptoms of either depression or sexual dysfunction. Hence, the following proposals are somewhat speculative; they are not strictly evidence-driven. With regard to improvements in sexual dysfunction, it is possible that agents of R. damascena oil have an antagonis￾tic effect on the stimulation of the postsynaptic 5-HT2 and 5-HT3 receptors30–32 and that these agents have an antago￾nistic effect on the corticolimbic 5-HT receptors, which are responsible for increasing sexual desire, ejaculation, and orgasm.34,35 Additionally, it is possible that the agents of R. damascena agonistically increase the release of dopamine and norepinephrine in the substantia nigra,31,32 as well as disinhibiting nitric oxide synthase.33 Further, R. damascena oil seems to have an antimicrobial effect, and has been reported to protect neurons against amyloid β toxicity, a major pathological component of Alzheimer’s disease, and to protect rats against seizures. More specifically, it is sug￾gested that the agent glycoside quercetin is also responsible for improving neuronal activity, probably by inducing the expression of synaptic proteins synaptotagmin and post￾synaptic density protein-95, at least in cultured rat cortical neurons.65 Likewise, quercetin has been shown to reduce behavioral deficiencies, restore astrocytes and microglia, and reduce serotonin metabolism in a 3-nitropropionic acid￾induced rat model of Huntington’s Disease.66 Last, Merzoug et al67 reported that quercetin mitigated Adriamycin-induced anxiety- and depression-like behaviors, immune dysfunction, and brain oxidative stress in rats. With regard to the glycoside kaempferol, evidence from animal studies has shown an antidepressant and modulating effect on brain-derived neurotrophic factor and b amyloid in the neurons and hippocampus of double TgAD mice.68 Overall, research on animal models suggest that both quercetin and kaempferol, two of the main agents of R. damascena oil, seem to have beneficial influences on symptoms of depression at the molecular level. Moreover, we also observe that explaining the occurrence and maintenance of MDD in terms of monoamine deficiency is just one of several putative pathways by which MDD might be explained neurophysiologically and neuroendocrinologi￾cally. In this regard, more recently efforts have been made to further investigate the roles of the neuropeptide brain￾derived neurotrophic factor on MDD,10,69,70 on ketamine,71 and statins.72–75 With regard to statins, by using a mouse model, Ludka et al16 observed that after acute atorvastatin treatment, the antidepressant effect seemed to be explained via the l-arginine-nitric oxide-cyclic guanosine mono￾phosphate pathway; atorvastatin seemed to inhibit NMDA (N-methyl-d-aspartatic acid) receptors and NO-cGMP (nitric oxide-cyclic guanosine monophosphate) synthesis, leading to a down-regulation of excitatory processes. On a behav￾ioral level, this down-regulation seems to be reflected in a reduction of symptoms of depression. However, it remains unclear to what extent the new pathways explaining MDD neurophysiologically and neuroendocrinologically may help to better understand the influence of the agents of R. damascena oil on both symptoms of depression and sexual dysfunction. Despite the encouraging results, several limitations should be considered to prevent overgeneralization of the data. First, as we have noted, neither the precise effects of the agents of R. damascena, nor their neurophysiological and neuroendocrinological influences on MDD and SSRI-I SD, are well understood. Accordingly, the details of the underly￾ing mechanisms remain, for the present, unresolved. Second, participants were selected and recruited from one study center; therefore, a systematic selection bias cannot be excluded. In this regard, third and most importantly, we cannot say whether an identical pattern of results would also have been observed with female patients. Fourth, the present pattern of results

Dovepress Rosa damascena oil for male SSRl-induced sexual dysfunction might have emerged because of other latent but unassessed 9.Kanfer FH,Reinecker H,Schmelzer D.[Self-management therapy: a textbook for clinical practicel.Selbstmanagement-Therapie:Ein psychological or physiological variables,which might have Lehrbuch fuir die klinische Praxis.5th ed.New York:Springer; biased two or more dimensions in the same direction.Fifth 2012. we relied on patients'self-ratings;this might be considered 10.Mota-Pereira J,Silverio J,Carvalho S,Ribeiro JC,Fonte D,Ramos J. Moderate exercise improves depression parameters in treatment- a limitation with regard to symptoms of depression,although resistant patients with major depressive disorder./Psychiatr Res.2011: the assessment of sexual function does commonly rely on 45(8):1005-1011. 11.Cooney GM,Dwan K,Greig CA,et al.Exercise for depression. self-ratings.However,future research should also include Cochrane Database Syst Rev.2013:9:CD004366. experts'ratings of symptoms of depression and global clinical 12.Mura G.Moro MF.Patten SB.Carta MG.Exercise as an add-on strategy impression.Sixth,other depression-related symptoms,such for the treatment of major depressive disorder:a systematic review. CNS Spectr.2014:19(6):496-508. as cognitive performance and psychosocial interaction,along 13.Stanton R,Happell B,Haymann M,Reaburn P.Exercise interventions with traits such as social attractiveness,"should be assessed. for the treatment of affective disorders-research to practice.Front Psychiatry.2014:5:46. Seventh,future studies might employ a more fine-grained and 14.Haghighi M,Salehi I,Erfani P,et al.Additional ECT increases BDNF- broader data collection approach with respect to patients'self- levels in patients suffering from major depressive disorders compared ratings and experts'ratings to allow detection of more subtle to patients treated with citalopram only.J Psychiatr Res.2013:47: 908-915. psychological changes.Last,given the strong associations 15.Kellner CH,Greenberg RM,Murrough JW,Bryson EO,Briggs MC. between depressive symptoms and sleep,future studies on Pasculli RM.ECT in treatment-resistant depression.Am /Psychiatry 2012:16912):1238-1244. this topic might also assess sleep patterns. 16.Ludka FK.Zomkowski AD.Cunha MP,et al.Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-argi- Conclusion nine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels.Eur Neuropsychopharmacol.2013:23(5): Evidence from this double-blind,randomized,and placebo- 400-412. controlled clinical trial shows that the administration of 17.Hasler G.Pathophysiology of depression:do we have any solid evidence of interest to clinicians?World Psychiatry.2010:9(3): R.damascena oil improved sexual dysfunction in male 155-161. patients suffering from both MDD and SSRI-I SD. 18.Bauer M,Pfennig A,Severus E,Whybrow PC,Angst J,Moller HJ; World Federation of Societies of Biological Psychiatry,Task Force on Unipolar Depressive Disorders.World Federation of Societies of Acknowledgments Biological Psychiatry (WFSBP)guidelines for biological treatment The present work is the doctoral thesis of Mehdi Shirzadifar. of unipolar depressive disorders,part 1:update 2013 on the acute and continuation treatment of unipolar depressive disorders.World./Biol We thank Gioia Schultheiss for text editing and Nick Emler Psychiatry.2013:145):334-385. (University of Surrey,UK)for proofreading the manuscript. 19.Hashimoto K.Emerging role of glutamate in the pathophysiology of major depressive disorder.Brain Res Rev.2009:61(2):105-123. 20.Castren E.Is mood chemistry?Nature Reviews Neuroscience.2005: Disclosure 6(3):241-246. The authors declare no conflicts of interest in this work 21.Cassano P,Fava M.Depression and public health-an overview. JPsychosom Res.2002:53(4):849-857. 22.Reichenpfader U,Gartlehner G,Morgan LC,et al.Sexual dysfunction References associated with second-generation antidepressants in patients with major 1.Josefsson T,Lindwall M.Archer T.Physical exercise intervention in depressive disorder:results from a systematic review with network depressive disorders:meta-analysis and systematic review.Scand./Med meta-analysis.Drug Saf.2014;37(1):19-31. Sci Sports.2014:242):259-272. 23.Graf H,Walter M,Metzger CD,Abler B.Antidepressant-related sexual 2.Murray CJ,Lopez AD.Global mortality,disability,and the contribu- dysfunction-perspectives from neuroimaging.Pharmacol Biochem tion of risk factors:global burden of disease study.Lancet.1997: Behav.2014:121:138-145. 349(90631436-1442. 24.Clark MS,Jansen K,Bresnahan M.Clinical inquiry:How do antide- 3.Johannes CB,Clayton AH,Odom DM,et al.Distressing sexual prob- pressants affect sexual function?JFam Pract.2013:62(11):660-661 lems in United States women revisited:prevalence after accounting for 25.Clayton AH,El Haddad S,Iluonakhamhe JP,Ponce Martinez C. depression.JClin Psychiarry.2009:70(12):1698-1706. Schuck AE.Sexual dysfunction associated with major depressive 4.Bonierbale M,Lancon C,Tignol J.The ELIXIR study:evaluation of disorder and antidepressant treatment.Expert Opin Drug Saf.2014; sexual dysfunction in 4557 depressed patients in France.Curr Medl Res 13(10:1361-1374. Opin.2003:192):114-124. 26. Rosen RC,Lane RM,Menza M.Effects of SSRIs on sexual function: 5.Angst J.Sexual problems in healthy and depressed persons.Int Clin a critical review.J Clin Psychopharmacol.1999:19(1):67-85 Psychopharmacol.1998:13(Suppl 6):S1-S4. 27.Serretti A,Chiesa A.Treatment-emergent sexual dysfunction related to 6.Kennedy SH,Rizvi S.Sexual dysfunction,depression,and the impact antidepressants:a meta-analysis.Clin Psychopharmacol.2009:29(3): of antidepressants.J Clin Psychopharmacol.2009:29(2):157-164. 259-266. 7.Clayton AH.El Haddad S,Iluonakhamhe JP,Ponce Martinez C. 28. Garlehner G,Hansen R,Thieda P,et al.Comparative Effectiveness of Schuck AE.Sexual dysfunction associated with major depres- Second-Generation Antidepressants in the Pharmacologic Treatment sive disorder and antidepressant treatment.Expert Opin Drug Saf. of Adult Depression:Comparative Effectiveness Review Number 7. 2014:13(10):1361-1374. Rockville:Agency for Healthcare Research and Quality.2007. 8.Grawe K.[Neuropsychotherapy].Neuropsychotherapie.Gottingen: Available at:www.effectivehealthcare.ahrq.gov/ehc/products/7/59/ Hogrefe:2004. Antidepressants_Final_Report.pdf.Accessed:March 5,2012. Neuropsychiatric Disease and Treatment 2015:II submit your 633 Dovepress

Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 633 Rosa damascena oil for male SSRI-induced sexual dysfunction might have emerged because of other latent but unassessed psychological or physiological variables, which might have biased two or more dimensions in the same direction. Fifth, we relied on patients’ self-ratings; this might be considered a limitation with regard to symptoms of depression, although the assessment of sexual function does commonly rely on self-ratings. However, future research should also include experts’ ratings of symptoms of depression and global clinical impression. Sixth, other depression-related symptoms, such as cognitive performance and psychosocial interaction, along with traits such as social attractiveness,41 should be assessed. Seventh, future studies might employ a more fine-grained and broader data collection approach with respect to patients’ self￾ratings and experts’ ratings to allow detection of more subtle psychological changes. Last, given the strong associations between depressive symptoms and sleep, future studies on this topic might also assess sleep patterns. Conclusion Evidence from this double-blind, randomized, and placebo￾controlled clinical trial shows that the administration of R. damascena oil improved sexual dysfunction in male patients suffering from both MDD and SSRI-I SD. Acknowledgments The present work is the doctoral thesis of Mehdi Shirzadifar. We thank Gioia Schultheiss for text editing and Nick Emler (University of Surrey, UK) for proofreading the manuscript. Disclosure The authors declare no conflicts of interest in this work. References 1. Josefsson T, Lindwall M, Archer T. Physical exercise intervention in depressive disorders: meta-analysis and systematic review. Scand J Med Sci Sports. 2014;24(2):259–272. 2. Murray CJ, Lopez AD. Global mortality, disability, and the contribu￾tion of risk factors: global burden of disease study. Lancet. 1997; 349(9063):1436–1442. 3. Johannes CB, Clayton AH, Odom DM, et al. Distressing sexual prob￾lems in United States women revisited: prevalence after accounting for depression. J Clin Psychiatry. 2009;70(12):1698–1706. 4. Bonierbale M, Lançon C, Tignol J. The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Curr Medl Res Opin. 2003;19(2):114–124. 5. Angst J. Sexual problems in healthy and depressed persons. Int Clin Psychopharmacol. 1998;13(Suppl 6):S1–S4. 6. Kennedy SH, Rizvi S. Sexual dysfunction, depression, and the impact of antidepressants. J Clin Psychopharmacol. 2009;29(2):157–164. 7. Clayton AH, El Haddad S, Iluonakhamhe JP, Ponce Martinez C, Schuck AE. Sexual dysfunction associated with major depres￾sive disorder and antidepressant treatment. Expert Opin Drug Saf. 2014;13(10):1361–1374. 8. Grawe K. [Neuropsychotherapy]. Neuropsychotherapie. Göttingen: Hogrefe; 2004. 9. Kanfer FH, Reinecker H, Schmelzer D. [Self-management therapy: a textbook for clinical practice]. Selbstmanagement-Therapie: Ein Lehrbuch für die klinische Praxis. 5th ed. New York: Springer; 2012. 10. Mota-Pereira J, Silverio J, Carvalho S, Ribeiro JC, Fonte D, Ramos J. Moderate exercise improves depression parameters in treatment￾resistant patients with major depressive disorder. J Psychiatr Res. 2011; 45(8):1005–1011. 11. Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;9:CD004366. 12. Mura G, Moro MF, Patten SB, Carta MG. Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review. CNS Spectr. 2014;19(6):496–508. 13. Stanton R, Happell B, Haymann M, Reaburn P. Exercise interventions for the treatment of affective disorders – research to practice. Front Psychiatry. 2014;5:46. 14. Haghighi M, Salehi I, Erfani P, et al. Additional ECT increases BDNF￾levels in patients suffering from major depressive disorders compared to patients treated with citalopram only. J Psychiatr Res. 2013;47: 908–915. 15. Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in treatment-resistant depression. Am J Psychiatry. 2012;169(12):1238–1244. 16. Ludka FK, Zomkowski AD, Cunha MP, et al. Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-argi￾nine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels. Eur Neuropsychopharmacol. 2013;23(5): 400–412. 17. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. 2010;9(3): 155–161. 18. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ; World Federation of Societies of Biological Psychiatry, Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334–385. 19. Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev. 2009;61(2):105–123. 20. Castrén E. Is mood chemistry? Nature Reviews Neuroscience. 2005; 6(3):241–246. 21. Cassano P, Fava M. Depression and public health – an overview. J Psychosom Res. 2002;53(4):849–857. 22. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. Drug Saf. 2014;37(1):19–31. 23. Graf H, Walter M, Metzger CD, Abler B. Antidepressant-related sexual dysfunction – perspectives from neuroimaging. Pharmacol Biochem Behav. 2014;121:138–145. 24. Clark MS, Jansen K, Bresnahan M. Clinical inquiry: How do antide￾pressants affect sexual function? J Fam Pract. 2013;62(11):660–661. 25. Clayton AH, El Haddad S, Iluonakhamhe JP, Ponce Martinez C, Schuck AE. Sexual dysfunction associated with major depressive disorder and antidepressant treatment. Expert Opin Drug Saf. 2014; 13(10):1361–1374. 26. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19(1):67–85. 27. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29(3): 259–266. 28. Garlehner G, Hansen R, Thieda P, et al. Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: Comparative Effectiveness Review Number 7. Rockville: Agency for Healthcare Research and Quality. 2007. 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Neuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 634 Farnia et al 29. Elnazer HY, Baldwin DS. Treatment with citalopram, but not with agomelatine, adversely affects sperm parameters: a case report and translational review. Acta Neuropsychiatr. 2014;26(2):125–129. 30. Segraves RT. Effects of psychotropic drugs on human erection and ejaculation. Arch Gen Psychiatry. 1989;46(3):275–284. 31. Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE. Lack of sexual dysfunction with the selective noradrena￾line reuptake inhibitor reboxetine during treatment for major depressive disorder. Int Clin Psychopharmacol. 2003;18(3):151–156. 32. Kanaly KA, Berman JR. Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunc￾tion. Curr Womens Health Rep. 2002;2(6):409–416. 33. Keltner NL, McAfee KM, Taylor CL. Mechanisms and treat￾ments of SSRI-induced sexual dysfunction. Persp Psychiatr Care. 2002;38(3):111–116. 34. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospec￾tive multicenter study of 1022 outpatients. J Clin Psychiatry. 2001;62: 10–21. 35. Balon R. SSRI-Associated Sexual Dysfunction. Am J Psychiatry. 2006;163(9):1504–1509. 36. Kennedy SH, Rizvi S. Sexual dysfunction, depression, and the impact of anti-depressants. J Clin Psychopharmacol. 2009;29(2):157–164. 37. Bull SA, Hunkeler EM, Lee JY. Discontinuing or switching selective sero￾tonin-reuptake inhibitors. Ann Pharmacother. 2002;36(4):578–584. 38. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959–965. 39. Maund E, Tendal B, Hróbjartsson A, et al. Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications. BMJ. 2014;348:g3510. 40. Nurnberg HG. An evidence-based review updating the various treatment and management approaches to serotonin reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147–168. 41. Sela Y, Shackelford TK, Pham MN, Euler HA. Do women perform fellatio as a mate retention behavior? Pers Individ Diffs. 2015;73: 61–66. 42. Buss D. Evolutionary Psychology: The New Science of Mind. Essex: Pearson; 2013. 43. Diamond J. The Third Chimpanzee: The Evolution and Future of the Human Animal. New York: HarperCollins Publisher; 1992. 44. Meston CM, Buss DM. Why Women Have Sex: Understanding Sexual Motivations from Adventure to Revenge (and Everything in Between). New York: Henry Holt and Company; 2009. 45. Miller G. The Mating Mind: How Sexual Choice Shaped the Evolution of Human Nature. New York: Random House; 2000. 46. Damis M, Patel Y, Simpson GM. Sildenafil in the treatment of SSRI￾induced sexual dysfunction: a pilot study. Prim Care Companion J Clin Psychiatry. 1999;1(6):184–187. 47. Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2013;5: CD003382. 48. Dolberg OT, Klag E, Gross Y, Schreiber S. Relief of serotonin selec￾tive reuptake inhibitor induced sexual dysfunction with low-dose mianserin in patients with traumatic brain injury. Psychopharmacology. 2002;161(4):404–407. 49. DeBattista C, Solvason B, Poirier J, Kendrick E, Loraas E. A placebo￾controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction. J Clin Psychiatry. 2005;66(7):844–848. 50. Segraves RT, Balon R. Sexual Pharmacology: Fast Facts. New York: WW Norton and Company; 2003. 51. Boskabady MH, Shafei MN, Saberi Z, Amini S. Pharmacological effects of rosa damascena. Iran J Basic Med Sci. 2011;14(4):295–307. 52. Chevallier A. The Encyclopedia of Medicinal Plants. London: Dorling Kindersely; 1996. 53. Rusanov K, Kovacheva N, Vosman B, et al. Microsatellite analysis of Rosa damascena Mill. accessions reveals genetic similarity between genotypes used for rose oil production and old Damask rose varieties. Theor Appl Genet. 2005;111(4):804–809. 54. Tabaei-Aghdaei SR, Babaei A, Khosh-Khui M, et al. Morphological and oil content variations amongst Damask rose (Rosa damascena Mill.) landraces from different regions of Iran. Sci Hortic. 2007;113: 44–48. 55. Basim E, Basim H. Antibacterial activity of Rosa damascena essential oil. Fitoterapia. 2003;74(4):394–396. 56. Shokouhinejad N, Emaneini M, Aligholi M, Jabalameli F. Antimicrobial effect of Rosa damascena oil on selected endodontic pathogens. Journal of the California Dental Association. 2010;38(2):123–126. 57. Awale S, Tohda C, Tezuka Y, Miyazaki M, Kadota S. Protective effects of rosa damascena and its active constituent on Aß(25–35)-induced neuritic atrophy. Evid Based Complement Alternat Med. 2011;149: 131042. 58. Ramezani R, Moghimi A, Rakhshandeh H, Ejtehadi H, Kheirabadi M. The effect of Rosa damascena essential oil on the amygdala electrical kindling seizures in rat. Pak J Biol Sci. 2008;11(5):746–751. 59. Loghmani-Khouzani H, Sabzi Fini O, Safari J. Essential oil composi￾tion of Rosa damascena mill cultivated in central Iran. Scientia Iranica. 2007;14(4):316–319. 60. Kumar N, Bhandari P, Singh B, Gupta AP, Kaul VK. Reversed phase￾HPLC for rapid determination of polyphenols in flowers of rose species. J Sep Sci. 2008;31(2):262–267. 61. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and valida￾tion of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. 62. American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington: American Psychiatric Publishing; 2013. 63. Mykletun A, Dahl AA, O’Leary MP, Fosså SD. Assessment of male sexual function by the Brief Sexual Function Inventory. BJU Int. 2006; 97(2):316–323. 64. Beck AT. Beck depression inventory. Philadelphia: Center for Cognitive Therapy; 1961. 65. Xu SL, Zhu KY, Bi CW, et al. Flavonoids induce the expression of synaptic proteins, synaptotagmin, and postsynaptic density protein-95 in cultured rat cortical neuron. Planta Med. 2013;79(18): 1710–1714. 66. Chakraborty J, Singh R, Dutta D, Naskar A, Rajamma U, Mohanakumar KP. Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-nitropropionic acid-induced rat model of Huntington’s disease. CNS Neurosci Ther. 2014;20(1):10–19. 67. Merzoug S, Toumi ML, Tahraoui A. Quercetin mitigates Adriamycin￾induced anxiety- and depression-like behaviors, immune dysfunction, and brain oxidative stress in rats. Naunyn Schmiedebergs Arch Phar￾macol. 2014;387(10):921–933. 68. Hou Y, Aboukhatwa MA, Lei DL, Manaye K, Khan I, Luo Y. Anti￾depressant natural flavonols modulate BDNF and beta amyloid in neurons and hippocampus of double TgAD mice. Neuropharmacology. 2010;58(6):911–920. 69. Mikoteit T, Beck J, Eckert A, et al. High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. J Psychopharmacol (Berl). 2014;231(15): 2955–2965. 70. Giese M, Beck J, Brand S et al. Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation. J Psychiatr Res. 2014; 59:1–7. 71. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depres￾sion and anxiety in patients receiving hospice care. J Palliat Med. 2010; 13(7):903–908