What Is Agomelatine?

Agomelatine, with a new trade name, is a chemical. The chemical name is N- [2- (7-methoxynaphthalene-1-yl) ethyl] acetamide, the molecular formula is C ₁₅ H ₁₇ NO ₂ , and the molecular weight is 243.3082. Agomelatine is an antidepressant and clinically treats adult depression.

Chinese name: Agomelatine
Foreign name: Agomelatine

CAS number: 138112-76-2
Molecular formula: C15H17NO2
Molecular weight: 243.3082

Agomelatine

Chinese name: agomelatine

Chinese alias: N- [2- (7-methoxynaphthalene-1-yl) ethyl] acetamide

English name: Agomelatine

English alias: 138112-76-2; Aglomelatine; N- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide; N- [2- (7-methoxynaphthalen-1-yl) ethyl) acetamide

CAS: 138112-76-2

Molecular formula: C ₁₅ H ₁₇ NO ₂

Molecular Structure:

Molecular weight: 243.3082 ^[1]

Density: ^[2]	1.109g / cm ³
Boiling point:	478.8 ° C at 760 mmHg
Melting point:	107-109 ° C
Flash point:	243.4 ° C
Exterior:	white solid

Basic information about agomelatine medication

Agomelatine traits

It is an orange-yellow film-coated tablet, which is white after removing the coating.

Agomelatine indications

It is used to treat adult depression ^[3] .

Agomelatine Specifications

25mg

Agomelatine dosage

The recommended dose is 25 mg once daily, taken orally before bedtime. If the symptoms do not improve after 2 weeks of treatment, you can increase the dose to 50mg once a day, that is, 2 tablets of 25mg each time, before bedtime. All patients should be examined for liver function at the beginning of treatment and regularly reviewed. It is recommended that periodic tests be performed at 6 weeks (at the end of the acute phase of treatment), 12 weeks, and 24 weeks (at the end of maintenance treatment). After that, it can be checked according to clinical needs. (See [Dimensional New Precautions]) Patients with depression should be given an adequate treatment cycle (at least 6 months) to ensure that symptoms completely disappear. Dimensional can be taken with food or on an empty stomach ^[3] .

Agomelatine adverse reactions

Common headaches, dizziness, drowsiness, insomnia, migraine; nausea, diarrhea, constipation, upper abdominal pain; sweating; back pain; visual fatigue and so on.

Agomelatine taboo

Patients who are allergic to the active ingredient or any excipients are contraindicated.
Hepatitis B virus carriers / patients, hepatitis C virus carriers / patients, and patients with impaired liver function (ie, patients with cirrhosis or active liver disease) are prohibited.
Dimension newly banned the combination with potent CYP1A2 inhibitors (such as fluvoxamine, ciprofloxacin) ^[3] .

Agomelatine Notes:

Medication for children and adolescents

The efficacy and safety of agomelatine in depression patients under the age of 18 have not yet been established, so it is not recommended that the dimension be newly used in the treatment of depression patients under the age of 18. In clinical trials conducted in children and adolescents, suicide-related behaviors (suicide attempts and suicidal thoughts), hostility (primarily manifested by aggressive, antagonistic behavior, and irritability) in patients receiving other antidepressants compared with placebo Incidence is higher ^[3] .

Medication for elderly patients with dementia

The efficacy and safety of Weixinxin for the treatment of elderly depression patients with dementia have not been proven. Therefore, Weixinxin should not be used for the treatment of elderly patients with depression.

Mania / hypomania

Agomelatine should be used with caution in patients with a history of manic or mild manic episodes. When patients have symptoms of mania, the use of dimensional new should be stopped.

Suicide / Suicide Thoughts

Depression itself leads to an increased risk of suicidal thoughts, injuries, and suicidal behaviors (suicide-related events). This risk persists until the patient is significantly relieved. Since there may be no improvement in the first few weeks or longer of treatment, patients should be closely monitored at this time until symptoms have resolved. The usual clinical experience is that the risk of suicide increases during the early stages of patient rehabilitation ^[3] .

Patients with elevated serum aminotransferase

In clinical trials, patients have experienced elevated serum transaminase levels when using agomelatine. After discontinuation of dimensional new, serum transaminase in these patients usually returns to normal levels. All patients should be tested for liver function before starting the new dimension therapy, and regularly reviewed during the treatment period. It is recommended that liver function tests be performed at 6 weeks, 12 weeks, and 24 weeks of treatment, after which it can be checked according to clinical needs. Patients with elevated serum aminotransferase levels should be reviewed within 48 hours. If the serum aminotransferase level exceeds three times the normal upper limit, medication should be stopped and liver function tests should be performed regularly until the normal level is restored.
Patients who drink excessive amounts of alcohol or are receiving drugs that may cause liver damage should be cautious with Dimension New.

Lactose intolerance

Dimension New contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose galactose malabsorption should not use Dimension New.

Impact on driving and mechanical operation capabilities

No new studies on the impact of dimensionality on driving and machine operation capabilities were conducted. But considering that dizziness and drowsiness are common adverse reactions of agomelatine. Patients should be aware of possible effects on their ability to drive and operate machinery.

Medication for pregnant and lactating women

Agomelatine should be used with caution in pregnant women. The potential impact of Latitude on breastfeeding infants is currently unproven. Patients should stop breastfeeding if they must be treated with agomelatine.

Medication for children

New safety and efficacy data on the use of dimensionality in children and adolescents under 18 years of age are currently lacking, so dimensionality is not recommended for children and adolescents under 18 years of age ^[3] .

Geriatric medication

The efficacy and safety of Weixinxin for the treatment of elderly patients with dementia associated with dementia have not been proven. Therefore, Weixinxin should not be used for the treatment of elderly patients with depression associated with dementia ^[3] .

Agomelatine drug interactions

Drug interactions that may affect agomelatine:
Agomelatine is mainly metabolized by cytochrome P4501A2 (CYP1A2) (90%) and CYP2C9 / 19 (10%). Drugs that interact with these enzymes may reduce or increase the bioavailability of agomelatine.
Fluvoxamine is a potent CYP1A2 and moderate CYP2C9 inhibitor, which can significantly inhibit the metabolism of agomelatine and increase the exposure of agomelatine by 60 times (range 12-412). Therefore, Dimension New prohibits the combined use with potent CYP1A2 inhibitors (such as fluvoxamine, ciprofloxacin).
When combined with estrogen (moderate CYP1A2 inhibitor), dimensional new exposure to agomelatine increased several times. Although none of the 800 concurrent estrogen patients showed specific safety issues, prior to further clinical experience, agomelatine and moderate CYP1A2 inhibitors (such as propranolol, gepafloxacin , Enoxacin) should be cautious.
Effects of agomelatine on other drugs In vivo studies: agomelatine has no induction effect on CYP450 isoenzymes. Agomelatine does not inhibit CYP1A2 enzymes (in vivo) and other CYP450 (in vitro). Therefore, agomelatine does not alter the exposure of drugs metabolized by CYP450.
Interactions with high plasma protein binding rate drugs:
Agomelatine has no effect on the free drug concentration of drugs with high plasma protein binding rates, and vice versa.
Other drugs:
No evidence of pharmacokinetic or pharmacodynamic interaction between agomelatine and other drugs that may be used in combination in the target population was found in phase I clinical trials, including benzodiazepines, lithium salts , Paroxetine, fluconazole and theophylline.
Alcohol: Dimension New cannot be used with alcohol at the same time.
Electroconvulsive therapy (ECT): There is no prior experience with ECT and agomelatine. Neither animal tests have shown convulsant properties of agomelatine. Therefore, it is considered that the simultaneous use of agomelatine and electroconvulsive therapy will not enhance the effect ^[3] .

Agomelatine overdose

Experience with agomelatine overdose is limited. During clinical development, several cases of agomelatine overdose have been reported, including taking alone (maximum dose to 450mg) or concurrently with other psychiatric medications (maximum dose to 525mg). Signs or symptoms of overdose are limited, including drowsiness ^[3] .

Agomelatine pharmacology and toxicology

Agomelatine is a serotonin 2C (S-HTx) receptor antagonist. The antidepressant mechanism may be related to the increase in neuronal plasticity and neuronal proliferation in the hippocampus. The immunostaining method was used to determine the proliferation, regeneration and death of neural cells in the brain of adult rats. It was found that long-term (3 weeks) administration of agomelatine can increase the proliferation of the hippocampal ventral dentate gyrus and neuron regeneration And this part is related to emotional reflection. No similar situation was seen at the time of acute or subacute administration (4 hours or 9 weeks). After prolonged administration, cell proliferation and neuron regeneration appeared in the entire dentate gyrus area, indicating that agomelatine can increase neural regeneration in the hippocampus to varying degrees, thereby generating new granule cells.
Depression patients often have difficulty falling asleep, waking up early, or changes in sleep rhythm. Polysomnography often shows reduced slow wave sleep (SWS), increased rapid eye movement sleep (REM) density or decreased latency, and decreased sleep ratio. Most antidepressants, such as tricyclic antidepressants (TCA) and selective 5-HT reuptake inhibitors (SSRI), have a regulatory effect on REM, but have a poor effect on non-REM sleep, especially SWS. Certain drugs with 5-HT2 receptor blocking effects, such as mianserine and nitrogen nitrogen, have the effects of promoting sleep and improving sleep continuity, but their blocking effects can cause drowsiness and daytime sleepiness. Agomelatine has a unique pharmacological mechanism that regulates the sleep-wake cycle, so it can regulate the sleep structure of patients at night and improve sleep ^[3] .

Agomelatine pharmacokinetics

1. Agomelatine is absorbed quickly and well after oral administration (80%). Absolute bioavailability is low (oral treatment dose <5%), and there are large differences among individuals. Compared with male individuals, females have higher bioavailability. Oral contraceptives increase the bioavailability of the drug, while smoking decreases the bioavailability. Peak plasma concentration was reached within 1-2 hours after taking the drug. 2. Within the therapeutic dose range, systemic exposure of agomelatine increases proportionally with increasing dose. At high doses, the first-pass effect becomes saturated. Eating (standard or high-fat diet) does not affect the bioavailability or absorption of agomelatine. High-fat diets increase individual differences ^[3] .

Agomelatine storage

Store in a sealed, cool and dry place ^[3] .

Agomelatine product uses

Melatonin

Agomelatine-Another blockbuster drug in the psychiatric category.

The melatonin analogue agomelatine is both the first melatonin receptor agonist and serotonin 2C (S-HTx) receptor antagonist. Animal tests and clinical studies have shown that the drug has antidepressant, antianxiety, sleep rhythm and biological clock effects. At the same time, it has fewer adverse reactions, no adverse effects on sexual function, and no withdrawal drug.

The first melatonin receptor agonist agomelatine (Valdoxan) is a melatonin analog, which is also a serotonin 2C (5-HTac) receptor antagonist. The affinity Ki of melatonin and its receptors MT1 and MT2 are 8.85x10-11 and 2.63x10-11, respectively. Agomelatine is similar to it, and it also has a high affinity for cloned human melatonin receptors MT1 and MT2 (Ki (6.15X10-11 and 2.68X10-11 respectively). Clinical studies have shown that agomelatine has a good effect on patients with depression and very few adverse reactions.

Agomelatine was developed by Servier and is currently on the market ^[3] .

Mechanism of agomelatine

The exact mechanism of agomelatine antidepressant is not clear. Pure 5-HT2C receptor blockers have no antidepressant effect. Agomelatine can block the 5-HT2C receptor. However, animal experiments have shown that melatonin also has a small amount of antidepressant effects. Studies have found that stress is related to melatonin secretion, but melatonin has not been seen in humans. Significant antidepressant effect.

Other studies have shown that the mechanism of agomelatine's antidepressant may be related to the increase in neuronal plasticity and neuronal proliferation in the hippocampus. The immunostaining method was used to determine the proliferation, regeneration and death of neural cells in the brain of adult rats. It was found that long-term (3 weeks) administration of agomelatine can increase the proliferation of the hippocampal ventral dentate gyrus and neuron regeneration And this part is related to emotional reflection. No similar situation was seen at the time of acute or subacute administration (4 hours or 9 weeks). After prolonged administration, cell proliferation and neuron regeneration appeared in the entire dentate gyrus area, indicating that agomelatine can increase neural regeneration in the hippocampus to varying degrees, thereby generating new granule cells.

Depression patients often have difficulty falling asleep, waking up early, or changes in sleep rhythm. Polysomnography often shows reduced slow wave sleep (SWS), increased rapid eye movement sleep (REM) density or decreased latency, and decreased sleep ratio. Most antidepressants, such as tricyclic antidepressants (TCA) and selective 5-HT reuptake inhibitors (SSRI), have a regulatory effect on REM, but have a poor effect on non-REM sleep, especially SWS. Certain drugs with 5-HT2 receptor blocking effects, such as mienserine, and nitrogen nitrogen, have the effects of promoting sleep and improving sleep continuity, but their blocking effects can cause drowsiness and drowsiness during the day. Agomelatine has a unique pharmacological mechanism that regulates the sleep-wake cycle, so it can regulate the sleep structure of the patient at night to improve sleep.

Agomelatine animal test

A large number of animal tests have proven that agomelatine has antidepressant, antianxiety, and adjusts the sleep cycle cyclic rhythm.

Because of the relationship between agomelatine and melatonin, people have begun to notice its role in regulating the circadian cycle of animals. Injecting agomelatine in rodents can reduce jet lag. Later studies found that agomelatine also has antidepressant and anxiolytic effects. For example, transgenic mouse animal model tests have shown that agomelatine has a similar antidepressant effect to desipramine Melanin similarly regulates the circadian rhythm. Experimental studies of chronic mild stress (CMS) depression in rat models suggest that continuous administration of agomelatine (10 and 50 mg / kg intraperitoneally) can reverse the induction of CMS The amount of sugar is reduced, and its effect is dose-dependent. The strength and duration of agomelatine are similar to those of imipramine or fluoxetine when administered at the same dose of 10 mg / kg intraperitoneally. Another depression animal model test for forced swimming in rats suggested that continuous administration of agomelatine for a single or 13 days could reduce the immobility time of model rats. Agomelatine showed a dose-dependent antidepressant effect when given continuously. The learned helplessness model test suggested that the administration of agomelatine 10mglkg once a day for 5 consecutive days can improve the defect of avoidance of learning. This effect is similar to that of imiprazole. Three animal model tests on anxiety suggested that the administration of agomelatine (10-75 mg / kg) in the morning and evening can increase the animal's responsiveness in the elevated cross maze test and the anxiety model test caused by Vogel conflict with drinking water, and the same at night The dose of melatonin can only increase the animal's open arm exploration, and has no response to the Vogel test. The conditional ultrasound vocal test showed that agomelatine can improve anxiety symptoms in model animals sooner or later, but melatonin has no similar effect. These results are all It is suggested that agomelatine has an anxiolytic effect. The results of another animal forced swimming test showed that agomelatine can strengthen the anxiolytic effect of diazepam ^[3] .

Clinical efficacy of agomelatine

A number of clinical studies have confirmed that agomelatine has obvious antidepressant effects, and has a faster onset of action, and has a better effect on depression and accompanying anxiety symptoms.

An eight-week international multicenter placebo-controlled study conducted by Lov et al in 2002 compared the efficacy of fixed-dose agomelatine with paroxetine. A total of 711 patients who met the diagnostic criteria for the fourth edition of the American Manual of Psychiatric Disorders (DSM-IV) Depression Disorder (MDD) were enrolled in the study. The patients were 18-65 years old. Patients received placebo, and after one week (to exclude those who responded to fast-acting doses) received agomelatine 1, 5, or 25 mg a day, or paroxetine 20 mg a day or continued to receive placebo. The pre-treatment Hamilton Depression r-Table (HAMD) score and Montgomery Depression Scale (MADRS) score of these patients were 27.4 and 31.5, respectively, with no significant difference between the groups. After 8 weeks of treatment, compared with the placebo group, the HAMID and MADRS terminal mean score evaluation showed that the agomelatine 25mg group and paroxetine group had significant antidepressant efficacy (P <0.05). The onset time of the latatin 25mg group was earlier than that of the placebo group (P '= 0.008). Significant differences between the groups were seen at the first week of medication (P <0.05), while the paroxetine group was not observed with the placebo group until the fourth week. The difference.

The study also evaluated depression and anxiety symptoms. Compared with the placebo group, the agomelatine 25mg group and paroxetine group significantly reduced the Hamilton Anxiety Scale (HAMA) score (P <0.05). It suggests that agomelatine may be similar to paroxetine, which can improve the anxiety associated with MDD patients. The reanalysis of patients with HAMD score 25 in this study showed that the effect of agomelatine 25mg group was significantly better than the placebo group {P <0.05}, while the paroxetine group was not significant compared with the placebo group. There was a difference (P = 0.09), suggesting that agomelatine may be more effective in treating more severe MDD than SSRIs such as paroxetine.

In 2005, two double-blind placebo parallel controlled studies conducted by Olie. MDD patients were randomized to receive agomelatine 25 mg a day or placebo. The dose was not increased to 50 mg a day for 6 weeks after 2 weeks. The results showed that agomelatine was significantly better than placebo, and the dose was increased to 50 mg a day to obtain a similar effect after 2 weeks, and it was well tolerated.

Similar double-blind placebo-controlled studies in 2007 had similar results. A total of 238 patients with moderate to severe MID were included in the study. The recipients were randomized to receive agomelatine (25 mg a day, taken in the evening, and increased to 50 m9 a day if the effect was not good after 2 weeks) or placebo for 6 weeks. The evaluation criteria are HAMD, clinical total impression scale improvement item (CGI-I) and clinical total impression scale severity item (CGI-S) scores. The results show that agomelatine is significantly better than placebo, with HAMD Compared with the terminal score, the difference between the two groups was 3.44 (P <0.001) in the agomelatine group and the placebo group. The CGI-1 and CGI-s scores also showed that the agomelatine group was better than the placebo group. (The differences between the groups were 4.45 and 0.50, respectively, and the P values were 0.006.) The effective rates of the two groups were 54.3% and 35.5% (P <0.05); the onset time of the agomelatine group was also earlier than the placebo group ( P = 0.008). Similar results were obtained in patients with major depression. In addition, the HAMD scale's mood and sleep item scores also showed that the agomelatine group was better than the placebo group. Agomelatine was well tolerated and both dose groups showed similar safety to placebo.

An open-label study by Pjrek et al. Confirmed that agomelatine is also effective for seasonal affective disorders. 37 patients with seasonal affective disorder with acute depressive episodes were given 25 mg agomelatine in the evening for 14 weeks, with HAMD rating scale structured interview guidance (SIGH-SAD), CGI-S, CGI-I, Circscreen The scale (a scale for self-assessment of sleep and circadian disorders) and the mild mania scale were evaluated. The results showed that the SIGH-SAD, CGI-S, and CGI-I scores of the patients decreased significantly after 2 weeks (P <0.001); the Circscreen score also significantly improved during the treatment process (P <0.001), and the amount of mild mania There was no significant change in the scores. In 14 weeks of treatment, 75.7% of patients achieved clinical improvement (SIGH-SAD score lower than 50% of the basic score), 70.3% achieved clinical recovery (SIGH-SAD score lower than 8), and only 1 patient had fatigue. Adverse reactions ^[3] .

Effects on sleep

Melatonin has a regulatory effect on sleep and the biological cycle rhythm. Whether agomelatine also has a similar effect has attracted people's attention, especially many patients with depression have sleep disorders. Animal tests have confirmed that agomelatine has a sleep regulating effect similar to melatonin. A study of outpatient MDD patients compared the efficacy of agomelatine 25-50 mg a day with venlafaxine 75--15 Dmg a day. The results show that the two are similar in the treatment of depression, but agomelatine The two items of the Leeds Sleep Assessment Questionnaire (LSEQ) scale (sleeping and sleep quality) were significantly improved compared to venlafaxine, and it was observed that this effect on improving sleep was manifested at 1 week after medication, and Daytime alertness has no effect.

Another open-label study evaluated the effect of agomelatine on sleep architecture in patients with MDD. Fifteen outpatient MDD patients with HAMD score 20 took agomelatine 25mg a day for 42 days. Sleep polysomnography studies were conducted on the 7th, 14th, and 42nd days. The results showed that the patients' sleep efficiency, the number of wake-ups after sleep and the total amount of SW5 all improved after 42 days of treatment, and the improvement of SWS at the beginning of the sleep cycle was particularly significant. From the 7th day, SWS decreased in the first 4 sleep cycles, and before the 14th day, the proportion of delta waves increased. There were no changes in REM latency, total volume, and density. It is suggested that agomelatine increases the continuity and quality of sleep, normalizes the distribution in the sleep cycle and the intensity of the 6 waves ^[3] .

Agomelatine safety and tolerability

Agomelatine has fewer adverse reactions, such as headache, nausea, and fatigue. No matter the short-term treatment or long-term maintenance treatment, the incidence of adverse reactions is similar to placebo, and the long-term treatment has fewer adverse reactions than short-term treatment. Some, this is similar to placebo. Agomelatine does not cause changes in body weight and has few gastrointestinal adverse reactions. Clinical studies performed by Loo have shown that the incidence of nausea in the paroxetine group was 17%, and that in the placebo group was 4.3%. The latatin 25mg group was only 2.9%. Statistical tests showed that agomelatine was similar to the placebo group, but significantly different from the paroxetine group.

The effects of antidepressants on sexual function have attracted considerable attention. TCA, SSRI, selective 5-HT, and norepinephrine reuptake inhibitors (SNRI) all have different effects on sexual function, but Agome Latine has a smaller effect on sexual function. Compared with venlafaxine, the evaluation of various psychological and physical symptoms of sexual function in the agomelatine group was superior to venlafaxine.

In 2004, Montgomery et al. Conducted a double-blind placebo-controlled study on withdrawal. MDD patients underwent double-blind treatment with agomelatine 25 mg a day or paroxetine 20 mg a day, and then 192 patients achieved sustained remission. Of patients were randomized into the continuation treatment group or the placebo group for 2 weeks, and the symptoms and signs scale (DESS) after discontinuation were evaluated in the first and second weeks, respectively. There was no significant difference in DESS scores between the two groups who discontinued agomelatine, indicating that there was little discontinuation of agomelatine, while the paroxetine group had obvious insomnia, dizziness, and nausea in the first week after discontinuation And myalgia and other reactions, these reactions disappear by the second week ^[3] .

Agomelatine conclusion

Agomelatine is the first melatonin receptor agonist with good antidepressant effect. Its onset of action is fast, and it has a good effect on depression and its accompanying anxiety, insomnia and other symptoms. It has fewer adverse reactions and high safety, and provides a new method for clinical treatment of MDD.

UK antidepressant study finds

According to a report published by British ABPI company titled "Targeting Depression", antidepressants that work simultaneously on three neurotransmitter systems and serotonin reuptake inhibitors with additional receptor activity are only Some of the new antidepressant drugs, and the other two compounds described in the report that have a "triple effect" that block the reuptake of dopamine, norepinephrine and serotonin are NeuroSearch. The company is in phase II clinical trials. Early trials of NS2389 and Organon's Ory-32782 in the preclinical development stage, the two compounds are currently highly expected.

Merck KgaA's EMD68843 is an antidepressant that combines selective serotonin reuptake inhibitor (SSRI) and other receptor activity. It has serotonin THT1A receptor partial agonist activity and is a selective 5 -Serotonin reuptake inhibitor (SSRI). It is believed to be the only compound that combines the above characteristics and may help provide more serotonin to stimulate these depression-related receptors, and is currently in a phase III / III clinical trial (recently reported YM992 from Japan's Yamanouchi is also in the phase II clinical trial, but it combines SSRI activity and the ability to block the 5HT2A receptor).

Since Myeth's venlafaxine was launched on the market in 1995, no other pure serotonin, a norepinephrine reuptake inhibitor, has been on the market. Later, although Eli Lilly has completed the expansion of duloxetine, it has not yet been approved for clinical use. Therefore, Mirtazapine from Orgnon has become the only one available on the market. To norepinephrine and serotonin selective antidepressants (NaSSA). Other companies exploring receptor subtypes include Astrazeneca, which has been reported to be evaluating a highly selective 5HT1A receptor inhibitor, NAD299 (in phase II clinical trials). It is believed that NAD299 has development potential in both depression and anxiety. Merck Sharp & Dohme is studying MK912, which interacts with two different noradrenaline receptors. However, Organon has Org-13011 and Org-12962, which stimulate the 5HT1A and 5HT2C receptors, respectively, both of which are in phase II clinical trials. There are two compounds of Sanofi-Santa-Labrador that are also in phase II clinical trials. They are SR46349 and SR142801, which block the 5HT2 receptor subtype, respectively. In addition, the company is also developing a 5HT2C receptor antagonist SB243213, which has just completed its Phase I clinical evaluation and has entered Phase II clinical trials. Other neurotransmitter systems under evaluation include substance P. Based on the P-substance antagonist CP96345, Pfizer has a series of compounds under development. CO96345 blocks neural activity in the blue spot (the area of the central nervous system (CNS) involved in mood regulation). Merck Sharp and Dohme also evaluated several P-substance antagonists in preclinical trials that showed similar levels of SSRI antidepressant activity. ^[3]