currently , virtually any psychiatric diagnosis is made through a combination of patient interviews , checklists , or self - report questionnaires , which rely on the symptoms coded in the diagnostic and statistical manual of mental disorders , either the fourth edition1 or the recently introduced fifth edition.2 yet , considerable debate exists about the actual validity of this sole symptom - based approach , thus sustaining the interest in objective biomarkers toward a better understanding of psychiatric disorders , including major depressive disorder ( mdd ) , and their pharmacological response.3 furthermore , a number of issues , including heterogeneous patients variables , high medical and psychiatric comorbidity rates , medications / triggers , inconsistency in specimen collection , storage and measurement protocols , and complexity of neuropsychiatric biological determinants of disorders , hinder the search for reliable biomarkers.4,5 ideally , a hassle - free biomarker reflecting the central nervous system ( cns ) functioning should provide a simplified , yet reliable , proxy measure of the activity of those neurotransmitters that are supposed to be involved in major psychiatric disturbances , to be flexibly applied both to clinical and healthy samples . among other approaches , the electroretinogram ( erg ) represents a relatively noninvasive , short , and cost - effective method developed to investigate the origin of a visual loss due to a retinal disease or injury , possibly representing a proxy of global cns activity of dopamine,6 a core monoamine in depression , directly or indirectly modulated by a number of antidepressant drugs with different pharmacodynamics.7 specifically , since the retina is part of the cns due to its embryonic origin , the erg has been used to investigate not only mdd , but also seasonal affective disorder , schizophrenia and bipolar disorder , autism spectrum disorders , and drug addiction,8 both in clinical and healthy samples exposed to different pharmacological agents,817 as well as in animal samples.6,18 of note , dopamine modulates different retinal functions , including counterbalancing of the synthesis of melatonin as measured with the erg.1921 melatonergic activity is also often impaired in the course of depressive episodes with prominent circadian rhythm disturbances , even if there is no antidepressant effect firmly documented for the hormone melatonin , neither for its analogue , ramelteon.2225 this seems quite puzzling considering that the recently released pro - melatonergic antidepressant agomelatine has been approved in europe for the treatment of mdd , though not in the us.26,27 a potential explanation for the claimed antidepressant effect of agomelatine should nonetheless be represented by its 5-hydroxytryptamine receptor type 2b ( 5-ht2b ) and 5-ht2c serotonergic antagonism,28 which may also promote the dopaminergic firing at the ventral tegmental area , frontal cortex , hypothalamus , hippocampus , medulla and pons , and also the retina , which is part of the cns as well,29 via enhancement of norepinephrinergic activity at the locus coeruleus.30 yet , while there is no question about the impact of melatonergic modulation on circadian rhythms relevant for mood as well as other core functions , the discrimination of the most plausible antidepressant effect of agomelatine between 5-ht antagonism versus melatonergic receptor type 1 ( mt1 ) and type 2 ( mt2 ) agonism remains elusive , at least with regard to just the simplified paradigm of dopaminergic modulation . additionally , ago - melatine has been proposed to indirectly modulate even the release of glutamate from prefrontal and frontal cortex and hippocampus,31,32 which further hinders the identification of a sole putative neurobiological pathway accounting for the claimed antidepressant effect of the drug . therefore , the aim of this preliminary study carried out on healthy volunteers was to assess the impact of agomelatine on retinal dopaminergic activity measured using standard erg recording , to provide a dissertation on the potential clinical implications of a differential neuropsychopharmacological erg trend eventually observed for agomelatine versus the trend already documented for melatonin . the light reaches the photoreceptors ( either cones or rods ) hosted at the outer segment of the retina after crossing the anterior segment of the eye , then is absorbed by the photopigment of the photoreceptors , which ignites the phototransduction process . in dark conditions , photoreceptors rest in a depolarized state , while the photon absorption leads to their hyperpolarization followed by the depolarization of the on bipolar cells . subsequently , the electric signal spreads to the ganglion cells , the axons of which reach the brain , mainly converging at the visual cortex . the retina also includes horizontal cells and amacrine cells , which are interneurons joining photoreceptors and bipolar cells , as well as the mller cells acting as glia.8 since dopamine represents a core retinal neurotransmitter involved in signal transduction , the erg should be a convenient technique by which to assess such dopaminergic activity both in light- and dark - adapted conditions,33 essentially by measurement of the  implicit time  and  amplitude  parameters of the b - wave,34 a trace component of the erg primarily determined by the bipolar cells.3537 any variation of the intensity or chromatic characteristic of the light stimulus could also be assessed by the erg , either for rods , cones , or mixed rod / cone photoreceptors functioning , thus allowing an objective quantitative measure of the retinal sensitivity to light.34 dopamine released by the amacrine and interplexiform cells38 interacts with the d1-like receptors ( namely , d1 and d5 subtypes ) at the horizontal , bipolar , amacrine , and ganglion cells , and with the d2-like ( d2 , d3 , and d4 ) receptors located at the retinal pigment epithelium cells , photoreceptors , and mller glial cells,3943 all of which are involved in the modulation of a number of retinal functions , including melatonin release.20 also , the daily synthesis and release of retinal dopamine , which is primarily influenced by lighting condition , follows a 24-hour rhythm,44 being influenced by the interaction between the amacrine and interplexiform dopaminergic neurons and photoreceptors . enhancement of dopamine activity via activation of d2-like receptors ( namely d4 ones ) located on photoreceptors inhibits the synthesis of melatonin , leading to subsequent inhibition of serotonergic n - acetyltransferase activity.45,46 in mammals , the d4 receptor accounts for the effects of the ligands on the whole d2 receptor family,42 either at the rods , cones , or retinal pigment epithelium,47 which , in turn , ultimately account for the impact of dopamine in the regulation of melatonin biosynthesis in vertebrate retina.48 substance p and dynorphin , which are expressed in d1 receptor - containing neurons , as well as preproenkephalin in d2 receptor - containing neurons , have also been used as monitors of dopaminergic activity in the cns,49 whereas there have been conflicting reports as to whether d1-like receptors are capable of increasing or decreasing the potassium efflux : d1-like agonists increase potassium current from chick retinal cells via an adenosine monophosphate ( amp)-independent mechanism , but inhibit this efflux in rat striatal neurons;50 as such , a conclusive understanding of the actual effect of d1 ( and possibly d5 ) stimulation or inhibition at the retina likewise remains elusive.51 melatonin suppresses the retinal release of dopamine via activation of its own melatonergic receptors ( primarily mt1 , but also mt2 and mt3 subtypes ) , widely distributed in the cns,52 including the retinal amacrine and interplexiform dopaminergic neurons.53,54 as mentioned previously , the b - wave response of the erg is influenced both by dopaminergic and melatonergic modulation . specifically , in daylight conditions , the b - wave response seems linked to cone dominance , possibly related to a shift toward a relative dominance of dopaminergic tone . on the contrary , under scotopic conditions , the b - wave response could be influenced by a relative dominance of rod tone,55 when the presence of circulating melatonin could account for rod dominance.56 erg studies carried out on healthy volunteers receiving melatonin , performed during conditions usually characterized by the absence of the hormone itself , showed a decline of cone response , either recorded as a decrease of the b - wave amplitude at 10 mg / day,57 or as a significant reduction of cones erg maximal response associated to a prolonged implicit time with 15 mg / day melatonin.58 concordant results were recently documented in animal samples exposed to high doses of melatonin during the day ( 90 mg / day in anaesthetized beagle dogs ) , showing a decrease of the photopic amplitude of both a- and b - waves , but no impact on the implicit time , which may indicate that the negative impact of melatonin on the photopic system may promote night vision.21 agomelatine shares the mt1 and mt2 agonism provided by melatonin , but not the agonism on mt3 receptors , with mt3 receptors having not been documented in mammalian samples.59 by blocking 5-ht2c receptors , agomelatine promotes the cns release of dopamine , possibly at the retina as well . however , at the time of writing , there are no available data whatsoever about the investigation of agomelatine using the flash erg in contrast to previous evidence for melatonin , this being the aim of this preliminary study . twenty - three healthy volunteers , both sexes , were enrolled at the department of neuroscience of the san martino hospital of genoa , genoa , italy , between september 2012 and march 2013 , upon approval by the local ethical committee and patient signatures on a valid informed consent form after procedures had been fully explained by the investigators ( either psychiatrists or neurologists ) . all procedures were carried out in accordance with the declaration of helsinki about human experimentation.60 no liver function monitoring was needed due to the prescription of just a single dose of agomelatine . in order to avoid any age - dependent effect affecting the b - wave amplitude,61 all subjects were aged between 22 and 35 years old . in addition , all subjects received the same single dose of agomelatine ( 25 mg / day ) , avoiding any concomitant medication to limit potential confounding biases as much as possible . similar considerations led to the inclusion of female subjects only during the luteal phase of the menstrual cycle ( objective measure of luteinizing hormone levels : range 120 iu / l ) in order to avoid an additional confounding factor potentially affecting the b - wave amplitude.62 finally , the baseline erg assessments ( with each session requiring about 1 hour for completion ) were performed according to the following scheme : 1 ) first erg recording at 10 am ( baseline = t0 ) , immediately followed by oral intake of agomelatine 25 mg ( one pill ) ; 2 ) 1 hour s rest ; 3 ) second erg recording ; 4 ) 1 ( more ) hour s rest ; 5 ) third ( final ) erg measurement . finally , a pictorial description of the standard erg has been provided in figure 1 along with a synthetic flow of study procedures in figure 2 . the electric signal was recorded binocularly ( dilated pupils ) using 9 mm silver / silver chloride skin disc electrodes placed on the lower eyelid ; the reference electrodes were placed close to the outer canthus of the eye and the ground electrode was placed on the forehead . the electrode impedance was maintained below 5 k in order to provide consistent results independent of the response yielded by skin electrodes with lower amplitude and higher noise levels with regard to either the corneal or conjunctival electrodes . the band - pass filter was set between 0.1 hz and 500 hz , and the subjects were dark - adapted for 20 minutes before recording . a full - field ganzfeld stimulator was used throughout the study , with the subjects seated in front of the stimulator bowl fixating on a point incorporated in the stimulus dome during each session . the dark - adapted 0.01 erg ( rod response ) was recorded using a dim white flash of 0.01 cdsm2 . after 10 minutes of light adaptation , the light - adapted 3.0 erg ( single - flash cone response ) was recorded , using a 3 cdsm2 stimulus with a background luminance of 30 cd / m2 measured at the surface of the full - field stimulus bowl . b - wave amplitude and time to peak ( implicit time ) were measured ( ms ) for all ergs . the a - wave amplitude was measured from baseline to a - wave trough , while the b - wave amplitude was measured from a - wave trough to b - wave peak ( v ) ; the a - wave and b - wave implicit times were measured from the time of the flash to the peak of each wave . demographic and descriptive analyses were carried out using the ibm spss software package ( v 21 ) for microsoft windows ( v 7 ) ( ibm corporation , armonk , ny , usa ) . since data follow a nonparametric distribution , as assessed by the shapiro  wilk test , friedman s analysis of variance was used in order to compare the median scores of the erg parameters . the light reaches the photoreceptors ( either cones or rods ) hosted at the outer segment of the retina after crossing the anterior segment of the eye , then is absorbed by the photopigment of the photoreceptors , which ignites the phototransduction process . in dark conditions , photoreceptors rest in a depolarized state , while the photon absorption leads to their hyperpolarization followed by the depolarization of the on bipolar cells . subsequently , the electric signal spreads to the ganglion cells , the axons of which reach the brain , mainly converging at the visual cortex . the retina also includes horizontal cells and amacrine cells , which are interneurons joining photoreceptors and bipolar cells , as well as the mller cells acting as glia.8 since dopamine represents a core retinal neurotransmitter involved in signal transduction , the erg should be a convenient technique by which to assess such dopaminergic activity both in light- and dark - adapted conditions,33 essentially by measurement of the  implicit time  and  amplitude  parameters of the b - wave,34 a trace component of the erg primarily determined by the bipolar cells.3537 any variation of the intensity or chromatic characteristic of the light stimulus could also be assessed by the erg , either for rods , cones , or mixed rod / cone photoreceptors functioning , thus allowing an objective quantitative measure of the retinal sensitivity to light.34 dopamine released by the amacrine and interplexiform cells38 interacts with the d1-like receptors ( namely , d1 and d5 subtypes ) at the horizontal , bipolar , amacrine , and ganglion cells , and with the d2-like ( d2 , d3 , and d4 ) receptors located at the retinal pigment epithelium cells , photoreceptors , and mller glial cells,3943 all of which are involved in the modulation of a number of retinal functions , including melatonin release.20 also , the daily synthesis and release of retinal dopamine , which is primarily influenced by lighting condition , follows a 24-hour rhythm,44 being influenced by the interaction between the amacrine and interplexiform dopaminergic neurons and photoreceptors . enhancement of dopamine activity via activation of d2-like receptors ( namely d4 ones ) located on photoreceptors inhibits the synthesis of melatonin , leading to subsequent inhibition of serotonergic n - acetyltransferase activity.45,46 in mammals , the d4 receptor accounts for the effects of the ligands on the whole d2 receptor family,42 either at the rods , cones , or retinal pigment epithelium,47 which , in turn , ultimately account for the impact of dopamine in the regulation of melatonin biosynthesis in vertebrate retina.48 substance p and dynorphin , which are expressed in d1 receptor - containing neurons , as well as preproenkephalin in d2 receptor - containing neurons , have also been used as monitors of dopaminergic activity in the cns,49 whereas there have been conflicting reports as to whether d1-like receptors are capable of increasing or decreasing the potassium efflux : d1-like agonists increase potassium current from chick retinal cells via an adenosine monophosphate ( amp)-independent mechanism , but inhibit this efflux in rat striatal neurons;50 as such , a conclusive understanding of the actual effect of d1 ( and possibly d5 ) stimulation or inhibition at the retina likewise remains elusive.51 melatonin suppresses the retinal release of dopamine via activation of its own melatonergic receptors ( primarily mt1 , but also mt2 and mt3 subtypes ) , widely distributed in the cns,52 including the retinal amacrine and interplexiform dopaminergic neurons.53,54 as mentioned previously , the b - wave response of the erg is influenced both by dopaminergic and melatonergic modulation . specifically , in daylight conditions , the b - wave response seems linked to cone dominance , possibly related to a shift toward a relative dominance of dopaminergic tone . on the contrary , under scotopic conditions , the b - wave response could be influenced by a relative dominance of rod tone,55 when the presence of circulating melatonin could account for rod dominance.56 erg studies carried out on healthy volunteers receiving melatonin , performed during conditions usually characterized by the absence of the hormone itself , showed a decline of cone response , either recorded as a decrease of the b - wave amplitude at 10 mg / day,57 or as a significant reduction of cones erg maximal response associated to a prolonged implicit time with 15 mg / day melatonin.58 concordant results were recently documented in animal samples exposed to high doses of melatonin during the day ( 90 mg / day in anaesthetized beagle dogs ) , showing a decrease of the photopic amplitude of both a- and b - waves , but no impact on the implicit time , which may indicate that the negative impact of melatonin on the photopic system may promote night vision.21 agomelatine shares the mt1 and mt2 agonism provided by melatonin , but not the agonism on mt3 receptors , with mt3 receptors having not been documented in mammalian samples.59 by blocking 5-ht2c receptors , agomelatine promotes the cns release of dopamine , possibly at the retina as well . however , at the time of writing , there are no available data whatsoever about the investigation of agomelatine using the flash erg in contrast to previous evidence for melatonin , this being the aim of this preliminary study . twenty - three healthy volunteers , both sexes , were enrolled at the department of neuroscience of the san martino hospital of genoa , genoa , italy , between september 2012 and march 2013 , upon approval by the local ethical committee and patient signatures on a valid informed consent form after procedures had been fully explained by the investigators ( either psychiatrists or neurologists ) . all procedures were carried out in accordance with the declaration of helsinki about human experimentation.60 no liver function monitoring was needed due to the prescription of just a single dose of agomelatine . in order to avoid any age - dependent effect affecting the b - wave amplitude,61 all subjects were aged between 22 and 35 years old . in addition , all subjects received the same single dose of agomelatine ( 25 mg / day ) , avoiding any concomitant medication to limit potential confounding biases as much as possible . similar considerations led to the inclusion of female subjects only during the luteal phase of the menstrual cycle ( objective measure of luteinizing hormone levels : range 120 iu / l ) in order to avoid an additional confounding factor potentially affecting the b - wave amplitude.62 finally , the baseline erg assessments ( with each session requiring about 1 hour for completion ) were performed according to the following scheme : 1 ) first erg recording at 10 am ( baseline = t0 ) , immediately followed by oral intake of agomelatine 25 mg ( one pill ) ; 2 ) 1 hour s rest ; 3 ) second erg recording ; 4 ) 1 ( more ) hour s rest ; 5 ) third ( final ) erg measurement . finally , a pictorial description of the standard erg has been provided in figure 1 along with a synthetic flow of study procedures in figure 2 . the electric signal was recorded binocularly ( dilated pupils ) using 9 mm silver / silver chloride skin disc electrodes placed on the lower eyelid ; the reference electrodes were placed close to the outer canthus of the eye and the ground electrode was placed on the forehead . the electrode impedance was maintained below 5 k in order to provide consistent results independent of the response yielded by skin electrodes with lower amplitude and higher noise levels with regard to either the corneal or conjunctival electrodes . the band - pass filter was set between 0.1 hz and 500 hz , and the subjects were dark - adapted for 20 minutes before recording . a full - field ganzfeld stimulator was used throughout the study , with the subjects seated in front of the stimulator bowl fixating on a point incorporated in the stimulus dome during each session . the dark - adapted 0.01 erg ( rod response ) was recorded using a dim white flash of 0.01 cdsm2 . after 10 minutes of light adaptation , the light - adapted 3.0 erg ( single - flash cone response ) was recorded , using a 3 cdsm2 stimulus with a background luminance of 30 cd / m2 measured at the surface of the full - field stimulus bowl . b - wave amplitude and time to peak ( implicit time ) were measured ( ms ) for all ergs . the a - wave amplitude was measured from baseline to a - wave trough , while the b - wave amplitude was measured from a - wave trough to b - wave peak ( v ) ; the a - wave and b - wave implicit times were measured from the time of the flash to the peak of each wave . demographic and descriptive analyses were carried out using the ibm spss software package ( v 21 ) for microsoft windows ( v 7 ) ( ibm corporation , armonk , ny , usa ) . since data follow a nonparametric distribution , as assessed by the shapiro  wilk test , friedman s analysis of variance was used in order to compare the median scores of the erg parameters . twenty - three subjects ( females n=8 or 35% of the sample ; males n=15 or 65% ) were included in the study and completed all the scheduled appointments and procedures . notably , among different measures of the b - wave parameters for both eyes ( including latency and amplitude either for cones or rods , and for erg maximal response ) , the only statistically significant modifications observed across the study were those related to cones b - wave amplitude and latency , in both eyes ( table 1 ) . finally , no statistically significant difference was observed for such parameters in males versus females . the absence of a control group , including differential doses of agomelatine , placebo , or melatonin , or depressed controls , make the present results merely indicative at this time . moreover , while dopamine could also affect the erg , its effect was basically observed in terms of changes in the retinal sensitivity.63 therefore , in this study , the lack of a luminance response function to measure retinal sensitivity with the erg prompts for caution in the interpretation of our preliminary findings . oscillatory potentials most likely generated by the dopaminergic neurons of the amacrine ( or interplexiform ) cells , should also be accounted for in replication studies . similarly , we followed the international society for clinical electrophysiology of vision ( iscev ) standard64 to record the erg , which represents the minimum standard flashes to be used to investigate the retinal function ( for patients with an eye disease ) ; however , in terms of mere research purposes , assessing the dynamic of retinal functioning over a wide range of intensities should allow a more reliable assessment of the retinal sensitivity . specifically , this latter consideration may have hampered the validity of the present preliminary protocol in the investigation of a possible impact of the erg . in our sample , agomelatine induced a slight , yet statistically significant , increase of the cones b - wave amplitude and latency in both eyes . while it may be argued that the above mentioned change in amplitude may actually be within the normal variation of the measure , this is nonetheless in contrast to previous reports5658 from comparable erg studies involving healthy subjects receiving melatonin . while both melatonin and agomelatine act on melatonergic receptors , the presence of 5-ht2c ( and 5-ht2b ) antagonism for the antidepressant drug should be prudently hypothesized to account for the differential trend observed at erg , eventually observed to play a role in the therapeutic effect claimed in depressed samples . notably , a previous polysomnographic study carried out on a small sample of healthy volunteers with the same dose of agomelatine ( 25 mg / day ) raised doubts about the actual blockade of 5-ht2c receptors in humans , based on the observation that this agent failed to increase slow - wave sleep , whereas potent 5-ht2c antagonists ( eg , cyproheptadine 4 mg , ritanserin 5 mg , olanzapine 5 mg , or mirtazapine 30 mg ) did.65 furthermore , in a recent animal study , neither the long - term administration of melatonin ( 40 mg / kg / day ) nor the selective 5-ht2c receptor antagonist sb 242084 ( 0.5 mg / kg / day ) had an effect on the firing rate and burst parameters of serotonergic and dopaminergic neurons . the combination of these latter mechanisms , however , enhanced only the number of spontaneously active dopaminergic neurons at the ventral tegmental area , while leaving the firing of the serotonergic neurons unaltered at the raphe dorsal nucleus . finally , the addition of a specific 5-ht2b antagonist ( ly 266097 at 0.6 mg / kg / day ) , which proved by itself to be devoid of effect , to the previous dual regimen increased the number of bursts per minute of dopaminergic neurons and the percentage of spikes occurring in burst , which ultimately mimics the effect of the antidepressant agomelatine.66 the absence of a control group , including differential doses of agomelatine , placebo , or melatonin , or depressed controls , make the present results merely indicative at this time . moreover , while dopamine could also affect the erg , its effect was basically observed in terms of changes in the retinal sensitivity.63 therefore , in this study , the lack of a luminance response function to measure retinal sensitivity with the erg prompts for caution in the interpretation of our preliminary findings . oscillatory potentials most likely generated by the dopaminergic neurons of the amacrine ( or interplexiform ) cells , should also be accounted for in replication studies . similarly , we followed the international society for clinical electrophysiology of vision ( iscev ) standard64 to record the erg , which represents the minimum standard flashes to be used to investigate the retinal function ( for patients with an eye disease ) ; however , in terms of mere research purposes , assessing the dynamic of retinal functioning over a wide range of intensities should allow a more reliable assessment of the retinal sensitivity . specifically , this latter consideration may have hampered the validity of the present preliminary protocol in the investigation of a possible impact of the erg . in our sample , agomelatine induced a slight , yet statistically significant , increase of the cones b - wave amplitude and latency in both eyes . while it may be argued that the above mentioned change in amplitude may actually be within the normal variation of the measure , this is nonetheless in contrast to previous reports5658 from comparable erg studies involving healthy subjects receiving melatonin . while both melatonin and agomelatine act on melatonergic receptors , the presence of 5-ht2c ( and 5-ht2b ) antagonism for the antidepressant drug should be prudently hypothesized to account for the differential trend observed at erg , eventually observed to play a role in the therapeutic effect claimed in depressed samples . notably , a previous polysomnographic study carried out on a small sample of healthy volunteers with the same dose of agomelatine ( 25 mg / day ) raised doubts about the actual blockade of 5-ht2c receptors in humans , based on the observation that this agent failed to increase slow - wave sleep , whereas potent 5-ht2c antagonists ( eg , cyproheptadine 4 mg , ritanserin 5 mg , olanzapine 5 mg , or mirtazapine 30 mg ) did.65 furthermore , in a recent animal study , neither the long - term administration of melatonin ( 40 mg / kg / day ) nor the selective 5-ht2c receptor antagonist sb 242084 ( 0.5 mg / kg / day ) had an effect on the firing rate and burst parameters of serotonergic and dopaminergic neurons . the combination of these latter mechanisms , however , enhanced only the number of spontaneously active dopaminergic neurons at the ventral tegmental area , while leaving the firing of the serotonergic neurons unaltered at the raphe dorsal nucleus . finally , the addition of a specific 5-ht2b antagonist ( ly 266097 at 0.6 mg / kg / day ) , which proved by itself to be devoid of effect , to the previous dual regimen increased the number of bursts per minute of dopaminergic neurons and the percentage of spikes occurring in burst , which ultimately mimics the effect of the antidepressant agomelatine.66 agomelatine may differ from melatonin not only in the absence of mt3 agonism , but also in the presence of a dual antagonism on 5-ht2c and 5-ht2b , which may corroborate the claimed clinical antidepressant effect and account for the increase of the b - wave amplitude and latency of the cones ( in daylight conditions ) . nonetheless , along with the abovementioned limitations urging much prudence in the interpretation of our results and the acknowledgement that a decline in the central serotonin activity may itself affect the cone b - wave latency , it pays to note that the  classical  paradigm of monoamines ( including dopamine ) as a core pathway involved in depression has been debated , shifting more attention toward impaired circadian rhythms in depression.67 therefore , with the ultimate goal of shedding further light on the mechanism of action of novel antidepressants , with agomelatine being the case in point , additional , more methodologically accurate erg studies on the matter are warranted .
backgroundagomelatine , the first melatonergic antidepressant , has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2c ( 5-ht2c ) antagonism , yet the impact of melatonergic agonism on this pathway is unclear . 
 previous studies employing simplified , yet reliable , proxy ( retinal ) measures of the central nervous system dopaminergic activity , namely the standard electroretinogram ( erg ) technique , suggested a reduction of the dopaminergic activity of the main erg parameter , the b - wave , by pure melatonin , notably a hormone devoid of any antidepressant activity . 
 therefore , the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b - wave trend at erg versus the effect exerted by pure melatonin , which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs.objective and methodsthe aim of the present preliminary erg study carried out on healthy volunteers ( n=23 ) receiving agomelatine was to explore the impact of this antidepressant drug on b - wave amplitude and latency of cones in daylight conditions using standard erg.resultsas postulated , agomelatine induced an enhancement of retinal dopaminergic activity , in contrast to what has been previously documented for melatonin.conclusiongiven the limits of this explorative study , especially the lack of a control group and that of a luminance response function to measure retinal sensitivity , further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of erg in discriminating between 5-ht antagonism and melatonergic ( mt ) agonism in relationship to the claimed antidepressant effect of agomelatine .