Levkovitz et al A Double-Blind, Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia Yechiel Levkovitz, MD; Shlomo Mendlovich, MD; Sharon Riwkes; Yoram Braw, PhD; Hana Levkovitch-Verbin, MD; Gilad Gal, PhD; Shmuel Fennig, MD; Ilan Treves, MD; and Shmuel Kron, MD Submitted: August 25, 2008; accepted November 24, 2008. Online ahead of print: November 3, 2009 (doi:10.4088/JCP.08m04666yel). Background: Current antipsychotics have only a Corresponding author: Yechiel Levkovitz, MD, The Emotion-Cognition limited effect on 2 core aspects of schizophrenia: nega- Research Center, The Shalvata Mental Health Care Center, POB 94. tive symptoms and cognitive deficits. Minocycline is Hod-Hasharon, Israel ([email protected]). a second-generation tetracycline that has a beneficial effect in various neurologic disorders. Recent findings in animal models and human case reports suggest its potential for the treatment of schizophrenia. These inocycline is a second-generation tetracycline that findings may be linked to the effect of minocycline on exerts anti-inflammatory and antimicrobial effects the glutamatergic system, through inhibition of nitric M 1 while having a distinct neuroprotective profile. It has excel- oxide synthase and blocking of nitric oxide–induced neurotoxicity. Other proposed mechanisms of action lent brain tissue penetration, is well tolerated, and is almost include effects of minocycline on the dopaminergic completely absorbed when taken orally. These properties, as system and its inhibition of microglial activation. well as its beneficial effect in animal models of neurologic Objective: To examine the efficacy of minocycline disorders, led investigators to suggest its potential in the as an add-on treatment for alleviating negative and treatment of schizophrenia.1,2 cognitive symptoms in early-phase schizophrenia. Method: A longitudinal double-blind, randomized, The therapeutic potential of minocycline was dem- placebo-controlled design was used, and patients were onstrated in recent studies using animal models of followed for 6 months from August 2003 to March schizophrenia. The “glutamate hypothesis” links schizophre- 2007. Seventy early-phase schizophrenia patients nia to a dysfunction in glutamatergic neurotransmission (according to DSM-IV) were recruited and 54 were via N-methyl-d-aspartic acid (NMDA) receptors.3 This randomly allocated in a 2:1 ratio to minocycline 200 mg/d. All patients had been initiated on treatment with is evident in the fact that administration of NMDA re- an atypical antipsychotic ≤ 14 days prior to study entry ceptor antagonists produces positive/negative symptoms (risperidone, olanzapine, quetiapine, or clozapine; 200– and cognitive impairments in healthy humans, while ex- 600 mg/d chlorpromazine-equivalent doses). Clinical, acerbating symptoms in schizophrenia patients.4,5 When cognitive, and functional assessments were conducted, using animal models based on the glutamate hypothesis, with the Scale for the Assessment of Negative Symp- toms (SANS) as the primary outcome measure. researchers found minocycline effective. For example, mi- Results: Minocycline was well tolerated, with few nocycline countered the disruptive effects of an NMDA adverse events. It showed a beneficial effect on nega- antagonist on visuospatial memory and sensorimotor gat- tive symptoms and general outcome (evident in SANS, ing.6 Similarly, minocycline attenuated behavioral changes Clinical Global Impressions scale). A similar pattern (eg, hyperlocomotion and prepulse inhibition deficits) and was found for cognitive functioning, mainly in execu- tive functions (working memory, cognitive shifting, the increase of dopamine in the frontal cortex and striatum 7 and cognitive planning). after administration of MK801 (an NMDA antagonist). In Conclusions: Minocycline treatment was associ- another study, minocycline was able to reduce cognitive dis- ated with improvement in negative symptoms and turbances induced by a different NMDA receptor antagonist executive functioning, both related to frontal-lobe (phencyclidine).8 activity. Overall, the findings support the beneficial effect of minocycline add-on therapy in early-phase These preliminary findings in animal models sparked schizophrenia. interest in minocycline’s potential for the aid of human Trial Registration: clinicaltrials.gov Identifier: schizophrenia patients. At this point, 2 preliminary studies NCT00733057 on schizophrenia patients were conducted. First, Miyaoka et J Clin Psychiatry 2010;71(2):138–149 al9 reported 2 published case reports of successful treatment © Copyright 2010 Physicians Postgraduate Press, Inc. of acute catatonic schizophrenia using minocycline (150 mg/d for 2 weeks, discontinued for 1 week and resumed 138 J Clin Psychiatry 71:2, February 2010 Minocycline vs Placebo in Early-Phase Schizophrenia afterward) added to antipsychotic treatment (haloperidol or characteristics with the cognitive symptoms of schizo- haloperidol and risperidone).9 The researchers concluded phrenia and (2) executive functions, which are involved in that after minocycline treatment the patients were prac- monitoring and regulating lower cognitive processes and in tically symptom free and that minocycline appears to be goal-oriented behaviors, such as planning, working mem- safe for use in patients with advanced schizophrenia. The ory, and problem solving.30 These cognitive functions are effects of minocycline were hypothesized to be related to its impaired in disorders that involve frontal hypofunctioning, action on the NMDA neurotransmitter system.10 Second, such as schizophrenia.31 Negative and cognitive symptoms Miyaoka et al11 reported the treatment with minocycline are correlated in schizophrenia patients and show simi- (adjunct to antipsychotic medication) of 22 schizophrenia larities in prevalence and course, as well as prognostic and patients in a 4-week open-label study (150 mg/d). There functional significance (although the nature of the relation- were no adverse events, and a clinical improvement was ship is still debated32). Moreover, negative symptoms and evident with the minocycline treatment, which was main- executive functions are both related to prefrontal function- tained at follow-up evaluation 4 weeks after the end of ing (ie, dorsolateral prefrontal cortex and the frontal medial minocycline treatment. The research team concludes that, cortex dysfunction).33 This fact is of importance since sev- “augmentation with minocycline may prove to be a viable eral lines of investigation revealed prefrontal alterations in strategy for ‘boosting’ antipsychotic efficacy and for treating schizophrenia. For example, volume reductions were found schizophrenia.”11(p287) in the prefrontal cortex of patients with schizophrenia,34,35 Minocycline may exert its effect through several possible and functional neuroimaging indicated hypofrontality to be mechanisms of actions. First, the efficacy of minocycline a characteristic of schizophrenia.36,37 This has a clear signifi- may be related to its effect of the glutamate pathway. cance since the frontal lobes have a key role in integrating Minocycline is a potent blocker of nitric oxide–induced the products of the other lobes, in emotional regulation and neurotoxicity.12,13 Glutamate, acting on NMDA receptors, high cognitive functions.38,39 is the principal activation signal for the production of The current study is a double-blind, placebo-controlled, nitric oxide.14,15 Activation of NMDA receptor leads to a randomized study of the effects of minocycline of execu- toxic calcium influx that activates numerous enzymes, tive functions and negative symptoms in schizophrenia. including neuronal nitric oxide synthase. Nitric oxide is These symptoms are only partially ameliorated by existing able to further increase the excitotoxicity by enhancing anti psychotic medications, a fact that has led to an ongo- glutamate release from presynaptic neurons and inhibit- ing effort by researchers to develop newer drug treatments ing glial glutamate transporters.16–19 Second, minocycline specifically aimed at alleviating these symptoms.40,41 To effects dopamine neurotransmission. Schizophrenia is as- the best of our knowledge, this is the first time that a more sociated with a dysregulation of dopamine functioning in comprehensive assessment of the efficacy and safety of mi- the prefrontal cortex and striatum.20 As indicated earlier, nocycline for the treatment of schizophrenia symptoms has pretreatment with minocycline attenuated the increase of been conducted. Such an investigation is needed in light of dopamine levels in the frontal cortex and striatum follow- the limited effect of existing antipsychotics and the promise ing administration of an NMDA antagonist.7 Minocycline that minocycline holds. also ameliorates the neurotoxicity caused by methamphet- We hypothesized that the effect of minocycline add-on amine,7,21 with a preliminary finding indicating its ability therapy would surpass that of treatment with atypical anti- to attenuate the reduction of dopamine transporters result- psychotics alone. We focused on patients in the early stage ing from methamphetamine treatment.22 Third, Miyaoka et of schizophrenia in light of findings indicating that early al11 suggest neurodegeneration as a possible focus for future pharmacologic intervention could improve the course of the research; apoptotic cell death is related to microglial activa- disorder.42 In addition, we aimed