An Ideal Antidepressant
Friday, September 29th, 2006An 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.
