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 DovepressNeuropsychiatric 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