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From Anecdotal Evidence to Proven Treatment: Testing Minocycline as a Treatment for Schizophrenia
Last week, we talked about the importance of and controversy surrounding off-label drug treatments. In another interesting case of this type, the National Institute for Health Research in the United Kingdom has just announced a 12-month clinical trial, which will start next month, studying the effects of the antibiotic minocycline (Minocin) in patients with schizophrenia.
Minocycline, a broad spectrum antibiotic, is typically prescribed to treat bacterial infections including urinary tract and respiratory infections, severe acne, gonorrhea, and others. While the mechanism of minocycline’s potential effects on schizophrenia symptoms is not clear, several observations over the past few years show helpful effects of the drug in patients when given in addition to ongoing therapy. Minocycline is listed by Torrey and Davis of The Stanley Medical Research Institute as one of 9 drugs that should be “repurposed” for treatment of schizophrenia and/or bipolar disorder due to its reported efficacy in patients who have not responded well to other medical treatments.
Medical cases have been published demonstrating significant improvements in patient delusions, hallucinations, and communication deficits 10-16 weeks after the start of minocycline treatment. This improvement lasted as long as the drug was given. Patients reported few to no side effects, and willingly continued treatment, several going on to lead productive lives outside of the hospital. Anecdotally, the importance of minocycline as treatment for schizophrenia was discovered in 2007 when a 23-year-old patient in Japan was admitted to the hospital with persecutory delusions and paranoia. The man had no previous documented history of psychiatric illness and all tests and scans taken at the time were normal. Initial treatment with haloperidol had no effect, but after developing pneumonia he was treated with minocycline which cleared the infection as well as the psychosis within two months. However, after completing the course of treatment for the infection the patient’s psychotic symptoms returned. Symptoms were again resolved when minocycline was re-prescribed.
Thus remains the big questions: what causes schizophrenia and how is minocycline working to improve the symptoms? There are several hypotheses as to the cause of schizophrenia currently in the works, but three major ones include: inflammatory processes in the brain, gross changes in brain metabolism, or neurochemical changes including glutamate hypofunction. Minocycline is known to be anti-inflammatory and inhibits the inflammatory enzyme 5-lipoxygenase. Brain imaging studies have suggested that minocycline treatment in patients reduces abnormal brain metabolism in specific regions of the brain, including the posterior cingulate gyrus. In addition, minocycline affects both types of glutamate receptors AMPA and NMDA. Neuronal administration of minocycline increases phosphorylation and expression of the AMPA receptor subtype GluR1, while it is neuroprotective against the neurotoxic effects of NMDA receptor antagonists. Both effects could lead to increased glutamatergic signaling, possibly contributing to improved cognitive functioning.
The UK trial will recruit 170 patients with early psychosis symptoms, half of whom will receive placebo, and half will receive daily minocycline in addition to their current therapies for 12 months. Brain imaging and blood measurements of inflammatory mediators will be used to determine effects of minocycline in the body, as well as monitoring of patients’ symptoms.
Other questions will remain, including the effects of long-term antibiotic use, both in contributing to antibiotic-resistant bacterial strains, and effects on the health of the patient.
Chaves C, de Marque CR, Wichert-Ana L, Maia-de-Oliveira JP, Itikawa EN, Crippa JA, Zuardi AW, Todd KG, Baker GB, Dursun SM, Hallak JE. (2010). Functional neuroimaging of minocycline’s effect in a patient with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. Apr 16; 34(3):550-2.
Kelly DL, Vyas G, Richardson CM, Koola M, McMahon RP, Buchanan RW, Wehring HJ. (2011). Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res. Dec; 133(1-3):257-8.