Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms (2015)
Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. Minocycline’s effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.
“There are no evidence-based treatments available for people who are partially or completely nonresponsive to CLZ and continue to have persistent symptoms. Lamotrigine is 1 medication that has some positive data adjunctive to CLZ on psychotic symptoms. However, its efficacy has been demonstrated in only 1 study and recently not been replicated; thus it remains questionable if it is an effective strategy. It is notable that lamotrigine added to other antipsychotics have not been effective, thus, if it has efficacy as an adjunct may possibly work synergistically through glutamatergic pathways. It is believed that lamotrigine functions as an ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) glutamate receptor modulator.”
Minocycline:
- crosses the blood-brain barrier and has recently been found to have an effect on the GluR1 AMPA receptor subtype
- is known to have anti-inflammatory actions and inhibits inflammatory enzymes
- directly inhibits the proliferation of, as well as attenuates, microglia activation
“Preliminary human studies in schizophrenia suggest potential benefits from minocycline. Initial case reports of minocycline-associated improvements in persistent psychotic symptoms led to an open-label 4-week study, which linked minocycline to mean reductions of over 50% in the Positive and Negative Syndrome Scale general psychopathology scale scores.A handful of recent clinical trial publications and a meta-analysis have report benefits (mostly negative symptoms) of minocycline, mostly in early episode and with medications other than CLZ.
Three small case reports, including one from our own group, have specifically reported symptom benefits from minocycline added to CLZ.The current study is the first double-blind, randomized controlled trial of adjunctive minocycline to CLZ in schizophrenia with persistent symptoms. We hypothesized that we would observe a significant improvement in positive and cognitive symptoms as well as that minocycline might have effects on negative symptoms (particularly avolition) and anxiety/depressive symptoms.”
“To date, there have been 4 published randomized, double-blind trials with minocycline, all finding some positive effects in cognitive function, negative symptoms, or positive symptoms but with differing inclusion and exclusion criteria and primary outcomes. In the first study published, Levkovitz et al studied minocycline as an adjunct treatment to treatment as usual for negative and cognitive symptoms in patients within the first 5 years of illness. The study of Chaudhry et al was a 2-site study with adjunct treatment of minocycline to treatment as usual in patients in the first 5 years of their illness but with both positive and negative symptoms as the primary outcomes. Liu et al studied adjunct minocycline to risperidone in patients in the first 5 years of illness but with negative symptoms as the primary outcome. Lastly, Khodaie-Ardakani et al also added minocycline to risperidone and with negative symptoms as the primary outcome but in a chronic population. This study that we present is different in that it is the first study with minocycline treatment as adjunct to CLZ, the first to have positive and cognitive symptoms as the primary outcomes and only the second to test in a chronic population. Our study failed to find significant results in positive and global cognitive symptoms and may not have been powered to find a difference in global negative symptoms. In secondary analyses, we did find significant improvements in the areas of avolition, working memory, and anxiety/depression.
Our prior case series of CLZ patients treated openly with adjunct minocycline reported improved positive symptoms but also improvements in motivation for social and school interactions and activities. Avolition is a core symptom of schizophrenia, which leads to a decrease in spontaneous, self-initiated, and purposeful behaviors observed in daily life activities. A unique domain within the negative symptom syndrome, avolition is often associated with poorer functional outcome. The domain of amotivation or avolition has been found to be a strong predictor of interpersonal relations and personal and social function. Avolition is thought to be due to aberrant cortical-striatal interactions that facilitate reward processing. Negative symptoms more generally have been found to be associated with higher levels of inflammation. Similarly, evidence of inflammation is more common in deficit versus nondeficit schizophrenia. Glutamate dysfunction may also underlie negative symptoms. The anti-inflammatory effects of minocycline and/or its modulation of glutamatergic pathways could underlie the avolition benefits we have observed. Although we observed a positive finding for avolition, the study may not have been powered to detect improvements in global negative symptoms.
Working memory is also regarded as a core deficit in schizophrenia.The improvements in working memory seen here are consistent with Levkovitz et al who also found improvements in working memory in early-phase schizophrenia patients, some of whom were taking CLZ. Working deficits have been found to be connected to inflammation. Liaury et al found that microglial activation was attenuated with related improvements in memory related to inflammation during minocycline treatment. Microglial cells are known to contribute to synaptic modulation, learning, and memory processes. Many other animal studies have found minocycline to reduce memory and working memory deficits in animal models.The relevance of this literature to the current results should be viewed with tempered enthusiasm given that the clinical importance of the modest but statistically significant improvement in working memory we observed is questionable”
Tolerability:
“Minocycline was well tolerated in this 10-week study. As noted, beneficial effects were noted in headache, constipation, and HDL levels. Changes in skin pigmentation were seen in a few participants; however, no one discontinued the study because of skin pigmentation. We also did not see gastrointestinal adverse effects or differences in weight gain, suggesting that minocycline could be tolerable as an adjunctive medication in a schizophrenia population. Other minocycline studies in schizophrenia also have had very good tolerability; however, in a few clinical trials, there have been gastrointestinal complaints such as nausea, diarrhea, and constipation that occurred more frequently with minocycline than in the placebo group, but most of these studies have used doses of up to 400 mg/d. In addition, it is important to point out that minocycline has been identified as a causative agent of drug-induced lupus (DIL), which has a similar presentation to systemic lupus erythematosus”
Conclusion:
“Our study is limited by small sample size, lack of power for negative symptoms, and the fact that change in functional outcomes from negative symptoms and cognitive improvements generally take longer than 10 weeks, as seen in longer term studies and case reports with minocycline,which have reported functional improvements. Nonetheless, our moderate effects in some treatment domains in a chronically ill and treatment-resistant population are worth noting. Our sample of CLZ-treated participants had undergone at least 6 months and commonly years of CLZ treatment, with partial improvement, but continued moderate to severe symptoms. This is a difficult to treat population with little evidence for efficacious adjunctive treatments. The current data and other published data continue to suggest that minocycline is a possible adjunctive medication. Future analyses of these data will examine inflammatory markers and imaging data to better evaluate biomarkers for treatment response. These data add to the growing evidence suggesting that minocycline is a worthwhile adjunct treatment to consider when first-line agents are not enough.”
See also:
advancingschizophreniatherapeutics 