About Your Brain Blog

Sleep disturbances are common among people that suffer from depression. Melatonin plays a major role in the regulation of sleep (1) and serotonin neurotransmission is a key target of many antidepressants. Thus, drugs that properly modify melatonin and serotonin signaling may yield an antidepressant that effectively treats more than one symptom of depression. Agomelatine (a.k.a. S-20098) represents the first generation of this atypical melatonergic/serotonergic class of antidepressants.

Agomelatine activates melatonin receptors (2, 3) and inhibits the serotonin 5-HT2C receptor (4). Preliminary clinical trials of Agomelatine for the treatment of depression have received favorable reviews in recent scientific publications (5, 6). In addition, there is also evidence that agomelatine causes anti-anxiety (anxiolytic) effects in animal models of anxiety (7). The pharmacological and behavioral properties of agomelatine warrant additional investigation as an effective alternative to other classes of antidepressants.

REFERENCES
(1) Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006) FEBS Journal 273:2813-38.
(2) Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, Caignard DH, Pfeiffer B, Delagrange P, Guardiola B, et al. (1994) Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Journal of Medicinal Chemistry 37:3231-9.
(3) Armstrong SM, McNulty OM, Guardiola-Lemaitre B, Redman JR. (1993) Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS). Pharmacology Biochemistry and Behavior 46:45-9.
(4) Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D. (2003) The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. Journal of Pharmacology and Experimental Therapeutics 306:954-64.
(5) Montgomery SA. (2006) Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist. European Neuropsychopharmacology 16 Supplement 5:S633-8.
(6) Kupfer DJ. (2006) Depression and associated sleep disturbances: patient benefits with agomelatine. European Neuropsychopharmacology 16 Supplement 5:S639-43.
(7) Papp M, Litwa E, Gruca P, Mocaer E. (2006) Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behavioral Pharmacology 17:9-18.

An ideal antidepressant, like any other medication, needs to be safe and effective. Antidepressants that target serotonin and/or norepinephrine neurotransmitter systems are generally regarded as relatively safe approaches to combat depression. Yet, people who suffer from treatment-resistant depression require alternate approaches to effectively treat depression.

What are the real-world expectations of an ideal antidepressant? Let’s examine the theoretical properties of a hypothetical antidepressant called UltAntiD. First, physicians found that administering UltAntiD to people that suffer from treatment-resistant depression resulted in a recovery rate of 75%. Although 100% would be ideal, 75% could be considered remarkable. Second, long term use of UltAntiD by the patients resulted in side effects that were not that different from other antidepressants.

Although UltAntiD appears to be an ideal hypothetical antidepressant, news headlines like “Crime Attributed to Delusional Properties of UltAntiD” and legal cases involving UltAntiD begin to appear throughout the country. Our society, including the minority population composed of physicians, lawyers, and people with legal prescriptions for UltAntiD, gradually established individual opinions as to whether UltAntiD is safe. Effectiveness was an issue only for the people that were meant to benefit from UltAntiD.

The imaginary case surrounding UltAntiD is not that different than some real-world, effective medications. Opioid-derivatives are effective painkillers with significant issues of abuse. Benzodiazepines are effective anti-anxiety drugs with significant issues of abuse. Would it be too far-fetched to think that effective antidepressants could have the potential for abuse?

Our need to address the complexities of depression and the possibilities for newer “atypical” antidepressants was recently examined by Neely Tucker at the Washington Post. The interesting article highlights a recent publication by Zarate et al. (1) that described the antidepressant-like effects of ketamine. It should be noted that earlier reports also documented antidepressant-like properties of ketamine (e.g. ref. 2).

Ketamine is in a class of compounds that block the function of NMDA receptors and therefore prevent signaling of glutamate, the major excitatory neurotransmitter in the brain. Technically, ketamine is considered a “noncompetitive NMDA receptor antagonist”, just like phencyclidine (PCP).
Ketamine and PCP are better known in the basic research community as agents that produce psychotic-like effects that model many, but not all, symptoms of schizophrenia (3,4).

The possibility that NMDA receptor activity represents a continuum, ranging from depression (hyperactive) to schizophrenia (hypoactive) is intriguing, but simplistic.

What should society accept as an ideal antidepressant?

REFERENCES
(1) Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63:856-64.
(2) Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. (2000) Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47:351-4.
(3) Jentsch JD, Roth RH. (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofuntion to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201-25.
(4) Goff DC, Coyle JT. (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. The American Journal of Psychiatry 158:1367-77.