Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia

Abstract

Treatment-resistant schizophrenia is a major health problem in the UK with the majority of patients treated with clozapine. In up to 70% of cases there is only a partial response to clozapine with continuing refractory symptoms. We describe two cases in a UK mental health service where minocycline was found to be useful and well tolerated as an augmentation agent with clozapine in the improvement of previously resistant positive and negative symptoms.

Keywords

Minocycline clozapine treatment-resistant schizophrenia

Introduction

Treatment-resistant schizophrenia is a major health problem in the UK with the majority of patients treated with clozapine. However in up to 70% of cases there is only a partial response to clozapine with refractory symptoms including those within the positive, negative and cognitive domains. In such cases a common strategy is to augment with another antipsychotic, the evidence for which is minimal at best (Sommer et al., 2011). Minocycline has previously been reported to be useful as an adjunct to antipsychotics in trials of schizophrenia not including clozapine (Miyaoka, 2008a).

We describe two cases in UK mental health services where minocycline was found to be useful and well tolerated as an augmentation agent with clozapine in the improvement of previously resistant positive and negative symptoms.

Case 1

Mr A is in his 20s. He had his first episode of paranoid schizophrenia in the summer of 2007. He is prescribed clozapine monotherapy at a stable dose (400 mg), after failing to respond to either risperidone or olanzapine, and with adequate clozapine serum levels (>0.4 mg/L). Mr A reported continued paranoid delusions, suspiciousness, low mood and apathy. These symptoms adversely affected his social functioning. He was unable to tolerate an increased clozapine dose due to marked weight gain, hypersalivation and sedation. Following the prescription of minocycline at 100 mg twice daily there was a sustained improvement in both positive and negative symptoms of schizophrenia as measured using the Brief Psychiatric Rating Scale (BPRS). The pre-minocycline BPRS score was 68 which fell to 54 after three months with most improvement seen in negative symptom scores. There were no other changes in treatment. Mr A also reported a subjective improvement in his mental health. He no longer restricted himself to the ward environment and began to attend group psychology sessions and social activities. There were no reported side effects. Following discontinuation of minocycline the previous symptoms re-emerged. Minocycline was later re-commenced with the same positive effect on symptoms with no reports of adverse effects.

Case 2

Mr B is in his 40s and has a diagnosis of paranoid schizophrenia. He has remained floridly psychotic for many years with severe paranoia and persecutory delusions. He was prescribed clozapine with therapeutic levels of greater than 0.8 mg/L. A range of different augmentation strategies had been tried unsuccessfully including typical and atypical antipsychotics. Following the addition of minocycline at 200 mg once daily, Mr B reported a noticeable reduction in both the frequencyand intensity of his hallucinations so that he felt subjectively less distressed. There were no other changes in medication or other treatments. The pre-minocycline BPRS score was 67and post-minocycline BPRS score at six weeks was 52 with most improvements observed within the positive symptoms domain.

Discussion

To the best of our knowledge these are the first case reports of the use of minocycline in treatment resistant schizophrenia with clozapine in the United Kingdom following case reports from North America (Kelly et al., 2011). In our cases minocycline was used as other augmentation strategies were either intolerable or ineffective in terms of objective or subjective improvement in resistant symptoms of schizophrenia. In both cases, following the introduction of minocycline, there were clinically significant reductions in BPRS scores associated with meaningful improvements in social functioning.

Several neurochemical abnormalities contribute to the development of schizophrenia and are related to the development of clinical symptoms. Most of the findings come from studies on dopamine and serotonin metabolism. Recently, other pathways have been implicated in the development of schizophrenia, in particular glutamatergic pathways and alterations in the activation of the inflammatory response system. For example in the glutamatergic pathway there is promising evidence that the N-methyl-D-aspartate (NMDA) receptor is compromised in treatment resistant schizophrenia (Bartolomeis, 2012). NMDA receptors are a major subtype of excitatory (glutamate) receptors and have an important role in working memory and attention. These and other cognitive functions are impaired in treatment-resistant schizophrenia. In terms of aberrant inflammatory mechanisms C-reactive protein (CRP) is an enzyme that is a marker of chronic inflammation. A number of studies have reported that CRP is elevated in individuals with schizophrenia, suggesting that inflammation is an important part of the disease process (e.g.: Fan et al., 2007).

We note that minocycline, a second generation antibiotic in the tetracycline class, possesses several anti-inflammatory properties. Evidence from animal and human studies have indicated that minocycline may have a potential role in the treatment of schizophrenia. In studies with animal models of psychosis, treatment with minocycline prevented or reversed the behavioural effects of administration of NMDA antagonists (Levkovitz et al., 2007; Zhang et al., 2004). Minocycline may reverse the biochemical and behavioural effects of NMDA antagonists and decrease production of cytokines and microglial activation, part of the inflammation response (Dean et al., 2012). It may also have neuroprotective properties (Miyaoka, 2008b). We speculate it is through these mechanisms that minocycline could improve symptoms in treatment-resistant schizophrenia.

Clearly further evidence is required and the authors are intending to trial the use of minocycline augmentation with clozapine in a future randomized control trial. At this stage the use of minocycline augmentation may be considered by clinicians as an augmentation option if other commonly used augmentation strategies have proven ineffective or intolerable.

Footnotes

Conflict of interest

The authors declare that there are no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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