Schizophrenia is a severe mental disorder associated with substantial morbidity and burden. For many individuals it causes a lifelong disability at immense cost to family and society [
1]. Schizophrenia is accepted to be a heterogeneous brain disorder with undetermined etiology. The conceptualization of schizophrenia has evolved over the past century, since its distinction from affective psychosis. The diagnosis rests on the combination of the occurrence of typical clinical features and longitudinal observation. Based on the clinical features, three overlapping dimensions of schizophrenia are identified: positive, negative, and disorganized [
2,
3]. These dimensions have a significant bearing on the course of the disorder: those with negative symptoms have poorer treatment response and more unfavorable course. Negative symptoms are particularly associated with various cognitive impairments that may lead to poor treatment response.
Although the introduction of antipsychotic medication almost half a century ago was undoubtedly a huge step forward in the treatment of schizophrenia [
4], a large proportion of patients fail to respond satisfactorily to trials with antipsychotic medications. For example, a study of 1,400 people with schizophrenia from 52 diverse sites across the United States found that only 14.5% participate in gainful employment, 12.9% report work in workshops or rehabilitation programs, and 72.6% reported no employment [
5]. In the past 15 years, several new medications called second generation or atypical antipsychotics have been introduced for the treatment of schizophrenia. These new generation antipsychotic medications have shown substantially fewer extrapyramidal side effects (EPSE) than first generation antipsychotic medications, which are the mainstay of treatment in low income countries like Ethiopia. However, these second generation antipsychotics are not shown to be clinically more effective than first generation antipsychotics [
6] and are associated with metabolic side effects. The only second generation antipsychotic medication which has been shown to be clinically more effective and to reduce rates of hospitalization is clozapine [
7,
8]. Moreover, the side effect burden of clozapine is high and clozapine is not available in many low income countries, including Ethiopia.
Preliminary data indicate that minocycline, a safe semi-synthetic tetracycline, may have neuroprotective properties and efficacy in improving negative symptoms of schizophrenia. Minocycline may be particularly relevant in low income countries, where it has been hypothesized that infectious agents contributing to the presentation of schizophrenia may be more common. In this study we aim to assess the efficacy of minocycline to alleviate symptoms of schizophrenia when given as an adjuvant to ongoing antipsychotic treatment.
Minocycline: nature
Minocycline is a tetracycline compound with activity as a broad spectrum bacteriostatic antibiotic. Minocycline is intrinsically more active against gram-positive than gram-negativemicro-organisms. It is also effective against micro-organisms such as rickettisia, coxiellaburnetti, mycoplasmapneuomniae, chlamydia species, legionella species, ureaplasma, some atypical mycobacteria, and plasmodium species. It is also active against many spirochetes, including borrelia burgdorferi (lyme disease) and treponema pallidum (syphilis). Minocycline inhibits bacterial protein synthesis by binding to the 30s bacteria ribosome and preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex [
9].
After an oral dosing, mincycline is almost completely absorbed and has a half-life of 16 to 18 h. It can therefore be administered less frequently and at lower doses. Importantly, unlike many other tetracyclines, food (including dairy products) does not interfere with the absorption of minocycline. It is significantly metabolized by the liver and is recovered from the urine and feces in lower amounts than other tetracyclines. The t1/2 of minocycline is not prolonged in patients with hepatic failure. The usual dose of minocycline is 100 mg every 12 h.
Minocycline is a well tolerated medication although some of the general side effects related to tetracyclines may occur. Gastro-intestinal irritation may occur but improves when administered with food. Hepatic toxicity typically develops in patients receiving large quantities orally. Minocycline may aggravate azotemia in patients with renal disease. Brown discoloration of teeth may also occur if given between the ages of 2 months and 5 years. Treatment with tetracycline during pregnancy may also be associated with tooth discoloration in the child. Patients taking minocycline may also experience some vestibular toxicity, manifested by dizziness, ataxia, nausea, and vomiting. Symptoms occur soon after the initial dose and usually disappear within 1 to 2 days after drug cessation. Hypersensitivity rarely occurs.
Minocycline for neurodegenerative diseases and schizophrenia
Minocycline has excellent penetration of the blood–brain barrier and is believed to modulate inflammatory processes linked to the pathophysiological mechanisms relevant to the onset or progression of neurodegenerative diseases [
10] and schizophrenia [
11].
Reviewing the potential benefits of minocycline in mental disorders and schizophrenia, four pathways, which were linked to the causation of mental disorders, have been proposed [
11]. The first mechanism is the calcium mediated glutamate excitotoxicity. Increased glutamate modulated intracellular calcium has been linked with mood and psychotic disorders, and minocycline was reported to reduce glutamate induced neurotoxicity in animal models. In one study, minocycline attenuated the behavioral changes following the administration of an NMDA antagonist in mice [
12]. In another study, minocycline reversed the effects of an NMDA antagonist in rats [
13]. The second mechanism highlighted relates to the antioxidant properties of minocycline. Minocylcine directly scavenges free radicals and inhibits molecules such as cyclooxygenase 2, induced nitric oxide synthase, and nicotinamide adenine dinucleotide phosphate oxidase. The third mechanism refers to the nuroprotective properties of minocycline, for example, through the caspase-independent anti-apoptotic effects including upregulation of antiapoptotic factor BCL-2 [
14]. The fourth pathway relates to the anti-inflammatory properties of minocycline. In a mechanism that seems to be distinct from its antimicrobial properties, minocycline has anti-inflammatory and neuroprotective properties [
15].
Even though the role of microgilia in the neruo-inlammatory process is not fully confirmed [
16], the anti-inflammatory activity of minocycline is attributed partly to its capacity to suppresses neuroimmune activation/proliferation of microglia as well as subsequent release of proinflammatory cytokines such as interleukins, IL-1β and IL-6, and tumor necrosis factor (TNF-α), neurotoxic substances such as nitric oxide, ROS, and chemokines [
14]. Furthermore, the cyoprotective activity of minocycline other inflammatory mediators such as the blockade of enzymatic activity of mitogen activated protein kinase 38 (P38 MAPK) which is thought to mediate inflammatory responses and cell death [
17,
18]. Minocycline is also linked with the inhibition of caspase-1 and caspase-3, which are involved in the generation of interleukin-1 and apoptosis, respectively [
19]. Minocycline is reported to suppress the release of lipids and the activity of matrix metalloproteases (MMPs), which disrupt the blood–brain barrier [
19]. Minocycline was also found to reduce prostaglandin-E2 (PGE2) formation and inhibit cyclo-oxygenase-2 (COX-2) expression in murine microglia and prostaglandin F2a (PGF2a) and PGE2 production induced by LPS in primary rat microglial cells [
11]. Minocycline has also been reported to have antiviral effects against HIV and antiprotozoal effects against
Toxoplasmagondii.
Its use in individuals with schizophrenia has been encouraged by its effects in rodent models of this disorder. Some preliminary data also suggest that minocycline may be useful in patients with schizophrenia. Two case report series have been published, one including two patients with schizophrenia [
20] and the other including three patients with recent-onset acute paranoid schizophrenia [
21]. An open label study of 22 patients with treatment-resistant schizophrenia, using minocycline 150 mg/d for 4 weeks, reported an improvement in both positive and negative symptoms [
15,
22]. Two double-blind trials have been carried out. In one study, 73 patients with schizophrenia of <5 years’ duration were randomized to minocycline 200 mg or placebo for 12 months: ‘all symptom measures improved significantly’ especially in the negative symptoms [
23]. In the other study, 54 ‘early phase’ (symptoms of <5 years) patients were randomized to minocycline 200 mg/d or placebo for 6 months; the authors reported a significant improvement in negative symptoms measured using Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression (CGI) and a significant improvement in some test of executive function [
24].
These initial findings encourage further replication. First, these studies are of comparatively small size. Second, in countries like Ethiopia where options for the treatment of schizophrenia are limited, identifying a safe alternative to clozapine is important. Related to this, most patients have limited exposure to psychotropic medications. Third, exposure to alcohol and substances is generally believed to be lower in the Ethiopian setting. Finally, given our hypothesis that infectious agents as a cause of schizophrenia may be more important in low income countries such as Ethiopia, minocycline may prove more useful. In this regard, the trial will help to explore the etiology of schizophrenia.
Study aim and objectives
The general aim of the study is to evaluate the efficacy and tolerability of minocycline as an adjuvant medication for patients with schizophrenia, who have failed to respond to an adequate trial of an antipsychotic medication defined as a dose equivalent to chlorpromazine of at least 200 mg per day given for a minimum of 4 weeks.
The specific objectives of the study are to determine the efficacy of minocycline added onto a standard treatment of schizophrenia in improving symptoms of schizophrenia (as measured by PANSS), global clinical state, negative symptoms of schizophrenia, and general functioning; and to assess the side effect burden of minocycline above and beyond standard antipsychotic medications.