|Year : 2015 | Volume
| Issue : 1 | Page : 6-12
Novel drugs in depression - A new hope
Chetan S Urade, Sunil M Mahakalkar, Ganesh N Dakhale, Mayur J Jadhav
Department of Pharmacology, Government Medical College, Nagpur, Maharashtra, India
|Date of Submission||18-Oct-2014|
|Date of Acceptance||13-Dec-2014|
|Date of Web Publication||27-Jan-2015|
Chetan S Urade
Vidyanagar, Civil Lines, Bramhapuri, Chandrapur - 441 206, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
According to the World Health Organization (WHO), depression is defined as a common mental disorder with symptoms of depressed mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, decreased sleep or appetite, and poor concentration. Beginning with the discovery of monoamine oxidase inhibitors (MOAIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are also developed as therapeutic measures for depression. However, management of depression is still challenging to clinicians as many adverse effects are found with these agents and some questions are still unanswered, creating a few lacunae to research. So to fulfill those lacunae, drugs, namely agomelatine, vortioxetine, vilazodone, and levomilnacipran extended release (ER) having different mechanisms have been recently approved by the United States Food and Drug Administration (FDA). Agomelatine helps in the normalization of disturbed circadian rhythm by melatonergic agonist action. Vortioxetine is a serotonin transporter (SERT) blocker with additional actions such as 5HT 3 and 5HT 7 receptors blockade. It is also an agonist of 5HT 1A and a partial agonist of 5HT 1B receptors. It is the first drug in the antidepressant class approved by FDA which has such multimodal actions. Vilazodone is approved by FDA considering its early onset of antidepressant actions. Levomilnacipran ER is an enantiomer of milnacipran, approved recently by FDA for the treatment of major depressive disorder (MDD). This review helps the clinician to choose better drugs according to patient's clinical needs. Significant efforts must be taken for conducting clinical trials assessing the efficacy of combination of drugs having different mechanisms such as agomelatine and vilazodone.
Keywords: Agomelatine, antidepressants, levomilnacipran extended release (ER), vilazodone, vortioxetine
|How to cite this article:|
Urade CS, Mahakalkar SM, Dakhale GN, Jadhav MJ. Novel drugs in depression - A new hope. Int J Nutr Pharmacol Neurol Dis 2015;5:6-12
|How to cite this URL:|
Urade CS, Mahakalkar SM, Dakhale GN, Jadhav MJ. Novel drugs in depression - A new hope. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2020 Mar 31];5:6-12. Available from: http://www.ijnpnd.com/text.asp?2015/5/1/6/150066
| Background|| |
According to World Health Organization (WHO), depression is defined as a common mental disorder that presents with depressed mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, decreased sleep or appetite, and poor concentration. Moreover, depression often comes with symptoms of anxiety. These comorbid conditions can become chronic or recurrent and lead to substantial impairment in an individual's ability to take care of his or her everyday responsibilities. 
Depression is estimated to affect 121 million people worldwide.  It is the third major cause of burden from disease and accounts for 4.5% of all human disability.  Depression will become second leading cause of disability for all age groups by 2020 and is expected to become the leading cause of disability in industrialized countries by 2030.  It is mostly predisposed by genetic influences, low self-esteem, chronic psychosocial adversities and lack of social and family support. 
Major depressive disorder (MDD) is a mental disorder characterized by low mood, low self-esteem, and loss of interest in normally enjoyable activities, the changes lasting for a minimum period of 2 weeks and causing impairment in social, occupational, sleeping and eating habits, general health, or other important areas of functioning.  MDD most commonly arises in the third decade of life. It is the leading cause of death by suicide. The lifetime prevalence is around 13% and incidence rate is of 4%.  The incidence of major depression is twice more in females than in males. MDD is a major cause of suicide in both sexes, nearly 90%. 
Though the various classes of antidepressants have already been approved by various drug controllers all over the world, treatment of depression still has numerous unmet needs, most of which are related to the efficacy and tolerability of currently available drugs. Most antidepressants cause sexual dysfunction, cognitive abnormality, and induce weight gain. These lead to treatment interruption which further increases the number of episodes and the risk of chronicity. Consequently, all these factors taken together increase the cost of depression at personal and community levels. Various novel drugs have been developed in recent years with different mechanisms in the hope of diminishing adverse effects of established antidepressants.
| Need of new antidepressants|| |
About 50 years ago, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs) came into existence.  TCAs such as imipramine, amitriptyline, desipramine are the inhibitors of neuronal transport (reuptake) of norepinephrine (NE) and serotonin (5HT), which leads to an antidepressant effect by increasing the level of NE and 5HT in the synaptic space. However, various evidences are now available for pharmacological actions of TCAs on additional receptors, i.e. histamine, muscarinic, α1 adrenergic receptors. TCAs block these receptors due to which patients have to face various side effects as given in [Table 1].
|Table 1: Side effects of tricyclic antidepressants and associated mechanisms |
Click here to view
In the last 20 years, new antidepressant classes came into existence, i.e. selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). These antidepressants have several advantages over TCAs such as absence of side effects of TCAs because of selectivity in action. However, continuous stimulation of these receptors leads to sexual dysfunction, gastrointestinal disturbances, weight gain, and somnolence. In addition to these, abrupt withdrawal leads to discontinuation syndrome which consists of nausea, vomiting, dizziness, restlessness, attacks of perspiration, and sleep disturbances. These side effects limit the use of SSRIs and SNRIs in the community. 
| Newer antidepressants|| |
Agomelatine (N-[2-(7-methoxynaphthalen-1-yl) ethyl] acetamide) is a unique class of antidepressants approved by the Drug Controller General of India (DCGI) on September 10, 2012 [Table 2].  It is an MT1 and MT2 agonist and 5HT 2c antagonist drug. Thus it shows both melatonergic and serotonergic modes of action.  This has given rise to melatonin agonist and selective serotonin antagonist (MASSA) concept.  The incidence of insomnia in depression is up to 80%. 
Mechanism of action
There are various evidences available suggesting that disruption of the circadian rhythm is an important underlying cause of MDD, and manifestations of the abnormal circadian rhythm in depression include delayed sleep, shortened latency to rapid eye movement sleep, fragmented sleep, and early waking. Also, amplitude of the circadian rhythm has been blunted in patients with depression and correlates with Hamilton Depression Rating Scale (HAM-D). Thus, normalization of circadian rhythm is a potential target in the treatment of depression.  Being a melatonergic agonist, agomelatine helps in normalization of disturbed circadian rhythm.
Bioavailability of agomelatine after oral administration is more than 78%. Food slows the absorption of agomelatine but it is clinically insignificant. Peak level in plasma is achieved 1-2 h after oral administration. Plasma protein binding is 95%, with 35% bound to albumin and 36% bound to α-1 acid glycoprotein. The volume of distribution is around 35 l. The major pathway of drug metabolism is by cytochrome P450 (CYP450) enzyme system. About 90% drug is metabolized by CYP450 isoenzyme1A2 (CYP1A2). Within the first 24 h, 61-81% drug is excreted as metabolites through the renal route. The elimination half-life of drug is 2-3 h. 
Efficacy of agomelatine
A 6-month pooled analysis (meta-analytic approach) is available in the literature comparing efficacy and tolerability of agomelatine with escitalopram, fluoxetine, and sertraline, which concludes that agomelatine is at least as efficacious as the investigated SSRIs with a trend to fewer discontinuations due to adverse events. 
Advantages of agomelatine over SSRIs are as follows:
- Agomelatine does not lead to discontinuation syndrome even in abrupt withdrawal after 12 weeks duration of therapy. (Discontinuation syndrome is associated with existing antidepressants)
- Suicidal tendencies, cardiovascular side effects (arrhythmias and hypotension), serotonin syndrome, and weight gain have not been observed
- Evidence is available in literature of fewer gastrointestinal disturbances and sexual dysfunctions
- Agomelatine improves the quality of sleep (onset of sleep, increases slow wave sleep) without daytime sedation.
Various side effects are observed in comparative studies such as headache, dizziness, nausea, fatigue, drowsiness (somnolence), dry mouth, and diarrhea. All these side effects are well tolerated and occur within the first 2 weeks of treatment. The most common adverse effects are dizziness and nausea. These adverse effects do not lead to cessation of therapy as they are transient in nature. 
Dosage and administration
Recommended dose is 25 mg, to be taken orally in the evening. After 2 weeks of treatment, if further clinical improvement is required, the dose may be increased to 50 mg once daily, taken as a single dose of two tablets in the evening. 
Cautions and contraindications
- Agomelatine is contraindicated in patients taking ciprofloxacin or fluvoxamine (potent inhibitors of CYP1A2), as these agents increase the plasma concentration of agomelatine
- Agomelatine is contraindicated in people with cirrhosis or active liver disease, as evidences are available in literature for rising liver enzymes levels due to long-term consumption of agomelatine ,
- Caution should be exercised in patients suffering from renal failure, as plasma levels of agomelatine may increase by 25% in patients with renal impairment
- Agomelatine should be discontinued in patients with symptoms of bipolar affective disorder, mania, or hypomania
- In pregnant and lactating women, agomelatine is to be used with extreme caution, as its effects on human fertility are unknown.
Vortioxetine is a novel class of antidepressant having multimodal type of actions: Serotonin transporter (SERT) blocker and a strong affinity for several serotonergic receptors [Table 2]. Its chemical name is 1- [2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide.  It shows pharmacodynamic antagonism by blocking 5HT 3 and 5HT 7 receptors. It is also an agonist of 5HT 1A and a partial agonist of 5HT 1B receptors. 
Mechanism of action
In vitro analysis
Vortioxetine is a 5-hydroxytryptamine (5HT) 3 , 5HT 7 and 5HT 1D receptor antagonist, partial agonist of 5HT 1B , agonist of 5HT 1A , and SERT inhibitor. Binding affinity and functional activities of vortioxetine are similar in rat and human brains. However, some differences exist such as 5HT 7 and 5HT 1A receptors are approximately one order of magnitude weaker in rat brain. Exvivo radiography experiments confirmed that lower doses (0.3-10 mg/kg) are required to occupy 5HT 3 receptor and higher doses are required to occupy 5HT 1B , 5HT 1A , and 5HT 7 receptors. 
In vivo analysis
Vortioxetine increases the extracellular concentration of serotonin in the medial prefrontal cortex and hippocampus (depression-related areas). This effect is found to be beneficial over SSRIs. Also, it increases the concentration of noradrenaline (NA), dopamine (DA), acetylcholine (Ach), and histamine in rat brain. 
Bioavailability of vortioxetine after oral injection is 75% with a t max of 7-8 h and a half-life (t 1/2 ) of 57 h. Vortioxetine achieves stable plasma concentration in <2 weeks. Plasma protein binding is 96%. Metabolism of vortioxetine is by CYP450 enzyme proteins such as CYP2D6, CYP3A4/5, CYP2C9, CYP2C19, CYP2A6, CYP2C8, and CYP2B6. 
Efficacy of vortioxetine
Main efficacy criteria in the comparative studies were change in the Montgomery-Asberg Depression Rating Scale (MADRS) or on the Hamilton Depression Rating Scale (HAM-D).  Of the seven efficacy trials for new episodes of depression, four were positive for vortioxetine versus placebo, ,,, while two studies showed no significant differences versus placebo, , with one failed study. 
Dosage and administration
The recommended starting dose is 10 mg administered orally once daily with or without meal. Once the dose is tolerated, it is increased to 20 mg. However, in known CYP2D6 poor metabolizers, the maximum recommended dose is 10 mg/day. Though the abrupt discontinuation is possible, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for 1 week prior to full discontinuation if possible. 
Vortioxetine is found to be a well-tolerated drug. However, in relevant studies, few side effects were found out such as nausea, vomiting, constipation, headache,  hyperhidrosis, and dry mouth.  The incidence of these side effects is >5%.  Sexual dysfunction and weight gain are important adverse effects of antidepressants having serotonergic activity such as SSRIs andSNRIs. ,, No study has stated such side effects being associated with vortioxetine.
- Hypersensitivity to vortioxetine
- MAOIs: Do not use MAOIs with vortioxetine or within 21 days of stopping treatment with vortioxetine. Also, do not use vortioxetine within 14 days of stopping an MAOI
- Administration of vortioxetine with linezolid or intravenous methylene blue is not recommended because of reversible monoamine oxidase inhibiting action of linezolid and methylene blue. 
Vilazodone (EMD68843, SB-659746-A)
Vilazodone is a novel antidepressant, which is a potent SSRI with partial 5HT 1A receptor agonist. , The chemical name is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl) butyl]-1-piperazinyl]-, hydrochloride (1:1).  Due to these combined actions of serotonergic facilitation across the brain's serotonergic pathways, authors described it as a serotonin partial agonist and reuptake inhibitor (SPARI). [Table 2]  It modulates the serotonergic activity at both pre- and postsynaptic SERTs. 
The advantage of vilazodone over conventional SSRIs is the earlier onset of pharmacological action which has led to better patient adherence to treatment and has ultimately resulted in enhanced therapeutic outcome. The partial agonistic activity at 5HT 1A receptor is thought to be responsible for the early onset of antidepressant action (within 1 week of starting dose administration).  Normally, conventional SSRIs pleiotropically stimulate presynaptic 5HT 1A autoreceptors. This will acutely decrease serotonin concentrations in the synapse. However, after chronic administration via desensitization procedure, stimulation of 5HT 1A receptor is overcome and SSRI is able to normalize serotonergic transmission. So, it is postulated that the causative factor for delayed pharmacological effect of SSRI is 5HT 1A autoreceptor stimulation. ,
Efficacy of vilazodone
Two trials (Phase III 8-week trial and 52-week trial) were held responsible for the FDA approval of vilazodone. In an 8-week trial, vilazodone shows statistically significant difference from placebo at eighth week with a least square mean difference (LSMD) of -3.2 points on the MADRS total score. At the first week, the patients on vilazodone showed statistically significant difference compared to placebo, suggesting early onset of action of vilazodone. In a 52-week trial, significant difference in vilazodone compared to placebo occurred starting at the sixth week. 
The absorption of vilazodone is significantly dependent on food (high-fat or light meal) as under fasting condition, the absorption is reduced by 50%. ,, C max is increased by approximately 147-160% and area under the curve (AUC) is increased by approximately 64-85%. , It is extensively metabolized primarily by hepatic CYP450 3A4 enzyme system, with a minor pathway of CYP2D6. Also, non-CYP mediated metabolism is involved such as carboxylase. The elimination of vilazodone is primarily via hepatic metabolism. Elimination half-life is about 25 h.  Due to its moderate half-life, withdrawal is possible with low severity of symptoms. Plasma protein binding is 96-99%, which may lead to displacement of digoxin and coumarin and increase their plasma concentration. Also, its use with MAOIs is not recommended. ,
Dosage and administration
As per the FDA sanctioned package insert, the recommended starting dose is 10 mg daily in the morning for 1 week, then escalated to 20 mg daily for the second week with the final titration to 40 mg/day as a usual daily dose. So in the market, three tablet strength are available i.e. 10 mg, 20 mg, and 40 mg. The 2-week titration period is to minimize the gastrointestinal discomfort that can occur with vilazodone.  As per the data, in renal and hepatic impairments, no dosing changes are required and to avoid serotonin syndrome, gradual withdrawal is suggested. 
The most common side effects reported so far are diarrhea, nausea, vomiting, headache, and insomnia. , The gastrointestinal adverse effects occur mostly in the first week of treatment. Decreased libido, abnormal orgasms, delayed ejaculation, and erectile dysfunction have been experienced by the patients due to vilazodone consumption, , which occurred in the first month of treatment and did not increase appreciably after that. 
Levomilnacipran extended release
Levomilnacipran extended release (ER) (1S, 2R-milnacipran, F2695) is a FDA approved drug, enantiomer of milnacipran, for the treatment of MDD. [Table 2]  Its chemical name is (1S,2R)-2-(aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride.  It is a potent SNRI with two fold greater potency for the inhibition of NE compared to 5HT reuptake. 
Mechanism of action
The exact mechanism of levomilnacipran is yet to be known. However, it is believed that levomilnacipran acts by enhancing 5HT and NE activity in the central nervous system via inhibition of reuptake at 5HT and NE transporters.  It also has an affinity for the NMDA/glutamate receptor (Ki 1.7 μmol/l). 
Efficacy of levomilnacipran
Three 8 week phase III trials are available in the literature, which concludes statistically significant difference of levomilnacipran over the placebo. The primary efficacy criteria was changed from the baseline in MADRS scores at the eighth week. ,,,
The bioavailabilty of levomilnacipran ER capsule is about 92% which is independent of food consumption. Maximum plasma concentration (C max -341 ng/ml) is achieved after 6-8 h of oral administration. The apparent volume of distribution is 387-473 l. It is primarily metabolized by hepatic CYP3A4 enzyme system and also by CYP2C8, CYP2C19, CYP2D6, and CYP2J2 but in minor contribution. The metabolites formed, namely, desmethyllevomilnacipran and p-hydroxylevomilnacipran, are conjugated with glucuronides. But both metabolites are inactive. The primary route of elimination for levomilnacipran and its metabolite is renal. The elimination half-life is ≈ 12 h. 
Dosage and administration
The recommended dose range of levomilnacipran ER is 40-120 mg once daily irrespective of food. The starting dose is 20 mg/day for 2 days, after that it is increased to 40 mg/day. Based on efficacy and tolerability, further increments of dose in the proportion of 40 mg/day every 2 or more days will decide. The maximum recommended dose is 120 mg/day. In case of moderate or severe renal impairment, patients must receive adjusted doses. However, in mild renal impairment and in mild, moderate, and severe hepatic impairment, there is no need of dose adjustments. 
The most common adverse effects are nausea, constipation, hyperhydrosis, increased heart rate, erectile dysfunction, vomiting, and palpitations. The incidence of all these adverse effects is ≥ 5% compared to placebo.  Levomilnacipran ER is associated with black box warning, which draws attention to the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants drugs. Therefore, it is contraindicated in children. 
- Levomilnacipran ER dose adjustment is recommended when co-administering with strong inhibitors of CYP3A4 (e.g. ketoconazole, erythromycin)
- Co-administration of levomilnacipran ER with alcohol is not recommended. Alcohol accelerates drug release from the body.
| Conclusion|| |
Since the 1950s, many treatment modalities for depression have been established. However, many questions remain unanswered like the normalization of disturbed circadian rhythm, early onset of antidepressant action, etc., This review of four recently-approved drugs helps clinicians to select the better drug according to clinical needs. Clinical studies regarding the agomelatine concluded that it helps in the normalization of disturbed circadian rhythm, and vilazodone can be used for early onset of antidepressant action. Vortioxetine and Levomilnacipran ER are found to be more efficacious than SSRIs in various clinical studies.
Significant efforts for conducting the clinical trials assessing the efficacy of combination of drugs having different mechanisms such as agomelatine and vilazodone may lead to better treatment options for MDD.
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[Table 1], [Table 2]