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How do psychotropic drugs work?
tions can cause parkinsonian-like movements, severe obesity (patients sometimes For decades, patients with psychiatric double in weight), diabetes, cardiovascular disorders such as schizophrenia have disease, and sedation. The side effects are been prescribed psychotropic drugs to so difficult to deal with that many patients alleviate their symptoms. Surprisingly, stop taking their pills. “If we had better scientists still do not fully understand drugs that more specifically treat the dishow these drugs work on a molecular ease and its pathology, then patients may level, so clinicians generally prescribe be more willing to stay on the medicamedications on a trial-and-error basis. tions,” says Bahn. To better inform our knowledge of this In the JPR study, the metabolic effects of process and ultimately develop medications with less severe side effects, Sabine Bahn and colleagues at the University of Cambridge, Imperial College London, and GlaxoSmithKline (all in the U.K.) conducted a metabolomics study. In JPR (DOI 10.1021/pr800892u), they report the metabolic changes induced by various psychotropic drugs in rat brains. To tailor drug therapy for patients with psychiatric disorders, a logical starting point might be to exploit what is already known about how these disorders develop. However, the molecular bases of the disorders are mysterious as well, says Bahn. “We don’t know what causes symptoms, so therefore we don’t have drugs that are specifically designed for the What’s on your mind? Researchers apply metabolomics diseasesand we don’t have animethods to learn how antipsychotics and mood stabilizers mal models that reflect the disease work in the brain. because we don’t know what causes it,” she explains. “So, we are in a vicious cycle and haven’t really made much progress over seven psychiatric drugs (five antipsychotics the last hundred years.” that are usually prescribed for the treatBecause all of these issues are interrement of schizophrenia and two mood stalated, an examination of drug action also bilizers that are prescribed for bipolar discould shed light on how psychiatric disorder) and one antiepileptic drug were orders develop, according to Bahn. The investigated. Some antipsychotics also are researchers’ assumption was that if the prescribed for bipolar disorder, so the redrug works well in patients, then it is searchers were interested to see whether affecting molecules that could be insimilar metabolites would be produced by volved in the disease process. So, if a these drugs. In addition, the two mood drug decreases the amount of a particustabilizers have antiepileptic properties. lar metabolite, then that metabolite’s However, not all antiepileptics have moodlevels may be aberrantly elevated in altering effects, so the antiepileptic drug patients. phenytoin was included in the study as a Another potential benefit from the innegative control. vestigation is the identification of molThe drugs were administered to normal ecules that are responsible for the extreme rats for 21 days, and then these rats and a side effects that most patients taking psycontrol group of rats were sacrificed. Tischotropic drugs experience. The medicasue from the frontal cortex, hippocampus,
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Journal of Proteome Research • Vol. 8, No. 4, 2009
and striatum of each rat was analyzed with NMR to quantify metabolite levels. Although each drug produced its own signature of metabolic changes, some drugs within the same class had similar responses. For example, most of the antipsychotics produced changes in the frontal cortex. Bahn points out that the frontal cortex is involved in the hallucinations and delusions that patients with schizophrenia typically experience. Also, the unique metabolic signatures suggest a reason why patients may respond to one drug and not another. The mood stabilizers and some of the antipsychotics had many similar effects, as expected. Unlike all of the other medications tested, the antiepileptic drug phenytoin induced changes only in the striatum. The results also revealed a few clues about mechanisms. Compared with control N-acetylaspartate (NAA) levels, the amounts of NAA were increased in the frontal cortices of rats given one of the mood stabilizers or one of the antipsychotics (except clozapine or olanzapine). Bahn says that NAA is a marker for neuronal integrity and that an increase in this metabolite could indicate that the neurons in the frontal cortex have increased viability. “In patients, we found NAA levels were also altered but in the opposite direction, so maybe these drugs are replenishing the lack of NAA in the diseased brain,” she explains. In addition, molecules involved in energy metabolism, neurotransmitter metabolism, and oligodendrocyte function were differentially regulated by various drugs. The real challenge for the researchers will be to integrate these metabolomics data with the gene expression and proteomics data they already have collected. This study is just one part of a larger project that is designed to address mechanistic issues by examining several types of samples, including cerebrospinal fluid and serum samples from humans and rats, says Bahn. —Katie Cottingham
10.1021/pr900128c
© 2009 American Chemical Society
