Inhibitors of the glycine transporter type 1 (GlyT1) are currently among the most promising substances for drug treatment of psychiatric disorders. Their application in schizophrenic disorders is the most developed, the GlyT1 inhibitor from Roche (Bitopertin®) is in clinical phase III trials.The starting point for this development were studies of Guochuan Tsai and co-workers with sarcosine. Sarcosine is a naturally occurring amino acid, a GlyT1 inhibitor, which has proven to be effective against all psychopathological dimensions in schizophrenia. The same group has now investigated the hypothesis that sarcosine – via facilitation of glutamatergic neurotransmission – should also have antidepressant properties. The researchers have recently published the results of their studies in rats and humans in the prestigious journal “Biological Psychiatry” (Huang et al., Biol Psychiatry 2013, 74: 734-741).
In a series of standard animal models of depression (forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, chronic unpredictable stress test) sarcosine was tested in rats. In these models, the compound showed properties, which are typical for antidepressants. But more important is a small randomized, double-blind treatment trial with two groups of 20 patients each with a depressive disorder with citalopram as a reference compound. The study was conducted in Taiwan. The treatment duration was six weeks. In the first two weeks of treatment, patients received either 20 mg citalopram or 500 mg sarcosine, in weeks 3 and 4 they were administered either 2 x 20 mg citalopram or 2 x 500 mg of sarcosine. In the last two weeks of treatment, there was the option of increasing the dose to 60 mg citalopram or 1500 mg of sarcosine. At the start of treatment, both groups of patients presented with about 24 points on the Hamilton Depression Rating Scale (HAMD), which translates into a moderate severity of depression.
The depression – as measured with the HAMD – was significantly more improved under sarcosine after two, four, and after six weeks compared to citalopram. After six weeks of treatment with citalopram the HAMD score had dropped to 14.0 points (baseline: 24.5), but with sarcosine to 9.4 points (baseline: 23.7). After six weeks, 14 of 20 patients treated with sarcosine fulfilled the criteria for treatment response, but only 4 out of 20 treated with citalopram. Only one patient who was treated with citalopram achieved a remission, but 13 of those treated with sarcosine. Both group differences were statistically significant (p = 0.004 and < 0.001). The tolerability of sarcosine was excellent, relevant adverse effects were not documented.
The authors conclude that their study suggests that sarcosine might be a very effective antidepressant treatment with rapid onset of action and few side-effects. The significance of the study is limited by the lack of a placebo arm and the high dropout rate in the citalopram arm. In any case, larger studies with placebo and active control appear justified.
However, we are far away from a profound understanding of the role of glutamatergic neurotransmission in mental disorders. How can it be explained that, on the one hand, ketamine as an NMDA receptor antagonist seems to be an effective antidepressant, but sarcosine, on the other hand, a substance which is believed to facilitate glutamatergic neurotransmission, has similar clinical activity?
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