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Letter to the Editor   |    
Adenosine and Antidepressant Effects of Sleep Deprivation
DIOGO R. LARA, M.D.; DIOGO O. SOUZA, M.D., PH.D.
Am J Psychiatry 2000;157:1707-a-1708. doi:10.1176/appi.ajp.157.10.1707-a

To the Editor: Joseph Wu, M.D., et al. (1) elegantly showed that 1) depressed patients who responded to sleep deprivation had higher relative pretreatment metabolic rates in the medial prefrontal cortex, ventral anterior cingulate, and posterior subcallosal cortex than nonresponders and normal volunteers and that 2) metabolic rates in the medial prefrontal cortex and frontal pole significantly decreased after sleep deprivation in responders. The authors suggested that dopaminergic and serotonergic systems may be involved in the effects of sleep deprivation.

We propose that the inhibitory neuromodulator adenosine may underlie the findings of this study. Adenosine inhibits excitatory neurotransmission and overall neuronal activity by acting on adenosine A1 receptors, which are widely distributed in the mammalian brain (2). Adenosine’s pivotal role in sleep modulation is strongly supported by the subjective and EEG-defined arousal produced by its antagonists, caffeine and theophylline, as well as by the fact that extracellular adenosine concentration is linked to neuronal metabolic activity (3). Regarding sleep deprivation specifically, it is noteworthy that 1) adenosine levels progressively increase after sustained, prolonged wakefulness in cats (3), 2) A1 receptor agonists mimic the electroencephalographic effects of sleep deprivation in rats (4), and 3) caffeine suppresses recovery sleep after deprivation (3). Therefore, the reduced metabolic rates observed in responders after sleep deprivation (1) are consistent with neuronal inhibition secondary to increases in extracellular adenosine. In addition, higher baseline metabolic rates in these patients may reflect a deficient adenosinergic inhibitory tone.

Additionally, Dr. Wu et al. (1) wondered if "the metabolic correlates of the antidepressant response to sleep deprivation…also characterize response to other forms of treatment such as antidepressant medications, ECT…." Again, seizures produce massive release of adenosine up to concentrations that may produce suppression of epileptic activity (5), and cAMP, which is thought to increase after treatment with antidepressants (6), can be released and degraded, elevating extracellular adenosine levels (2).

Finally, if adenosine contributes to the antidepressant effects of sleep deprivation, adenosine agonists, which are not yet available for clinical use, would also produce rapid antidepressant effects in a subset of patients.

Wu J, Buchsbaum MS, Gillin JC, Tang C, Cadwell S, Wiegand M, Najafi A, Klein E, Hazen K, Bunney WE Jr, Fallon JH, Keator D: Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry 1999; 156:1149–1158; erratum 156:  1666
 
Brundege JM, Dunwiddie TV: Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv Pharmacol  1997; 39:353–391
[PubMed]
 
Porkka-Heiskanen T, Strecker RE, Thakkar M, BjØrkum AA, Greene RW, McCarley RW: Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997; 276:1265–  1268
 
Benington JH, Kodali SK, Heller HC: Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res  1995; 692:79–85
[PubMed]
[CrossRef]
 
During MJ, Spencer DD: Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann Neurol  1992; 32:618–624
[PubMed]
[CrossRef]
 
Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16:2365–  2372
 
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References

Wu J, Buchsbaum MS, Gillin JC, Tang C, Cadwell S, Wiegand M, Najafi A, Klein E, Hazen K, Bunney WE Jr, Fallon JH, Keator D: Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry 1999; 156:1149–1158; erratum 156:  1666
 
Brundege JM, Dunwiddie TV: Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv Pharmacol  1997; 39:353–391
[PubMed]
 
Porkka-Heiskanen T, Strecker RE, Thakkar M, BjØrkum AA, Greene RW, McCarley RW: Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997; 276:1265–  1268
 
Benington JH, Kodali SK, Heller HC: Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res  1995; 692:79–85
[PubMed]
[CrossRef]
 
During MJ, Spencer DD: Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann Neurol  1992; 32:618–624
[PubMed]
[CrossRef]
 
Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16:2365–  2372
 
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