Negative and Cognitive Symptoms in Schizophrenia Clinical Trial
Official title:
A Double Blind Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia
Current antipsychotics have only a limited effect on two core symptoms of schizophrenia, negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline which has a beneficial effect in various neurological disorders. Recent findings in animal models and human case-reports suggest its potential for the treatment of these symptoms of schizophrenia. The current study aims to examine the efficacy of minocycline as add-on treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia. The study will utilize a longitudinal double blind, randomized, placebo-controlled design with patients followed for six-months. Early-phase schizophrenia patients were recruited and randomly allocated to a minocycline or placebo treatment (2:1 ratio; 200 mg/day). The primary outcome measures are the Scale for Assessment of Negative Symptoms (SANS) and assessments of executive functions.
Schizophrenia is a disorder characterized by disturbances in perception, thought, volition,
socialization, psychomotor behavior and the sense of self. Although patients suffer from
schizophrenia start from a point of relative normalcy or subtle impairment, following formal
onset most patients experience, to some degree, clinical deterioration. This deterioration
is manifest by the development of and increasing severity and persistence of psychotic and
negative symptoms, cognitive impairment, and diminished social and functional capacity. The
underlying causes of this clinical deterioration are not known, but is generally attributed
to progression of the illness and associated with periods of active positive symptoms. The
deterioration occurs primarily in the early stages of the illness and it is generally
confined to the first 5 years after onset. It also does not progress in a linear fashion.
Rather, after a period, patients stabilize at a level where they have persistent symptoms
and are impaired in their social and vocational function. Despite the heterogeneity of
symptoms among patients and their variability within patients across episodes, two distinct
patterns have been discerned in long-term catamnestic studies of schizophrenia patients.
First, negative symptoms tend to be less common and severe in the early stages of the
illness and to increase in prevalence and severity in the later stages. In the early stages
positive symptoms are more likely to dominate the clinical picture. Second, within the
constellation of positive symptoms, formed or systematized delusions and hallucinations are
more common in the earlier stages of illness, whereas thought disorganization, inappropriate
affect, and motor symptoms are more common in the later stages of illness.
Both MRI and MRS offer evidence, which is consistent with a neurodegenerative pathologic
process in schizophrenia that occurs primarily but not exclusively in the early stage of the
illness. Recent MRI studies of first-episode and childhood-onset schizophrenia samples using
more rigorous and standardized methods have found cortical gray matter and ventricular
system volume changes. The findings of volume reductions in cortical gray matter and
increases in ventricular system volume can be described as consistent with a process causing
pathomorphologic progression and neurodegeneration Investigators have considered the role of
molecular mechanisms in the neuropathology of schizophrenia. In this context, proponents of
neurodegenerative theories have suggested that the absence of gliosis and evidence of cell
degeneration could be due to the fact that the pathophysiology involves a graded apoptosis
rather than a fulminant necrotic process. Apoptosis is evanescent and difficult to detect
histopathologically before or after the process unfolds. Studies have shown that various
neurochemical events at the synapse can induce apoptosis. Such triggering actions include
excessive glutamate stimulation, calcium influx reactive oxygen species all of that can
induce caspase activation in dendrites. Local activation of caspases that initiate the
apoptotic cascade can spread to the cell body or remain localized producing
neurodegenerative synapse loss and synaptic remodeling. The reduced size and increased
density of neurons, in the absence of decreased numbers of neurons or glia and decreased
cortical thickness, indicate that cell processes and synaptic connections are reduced in
schizophrenia. This is consistent with reports of decreased concentrations of synaptic
proteins (e.g., synaptophysin). These cell processes and synapses could be lost as a
consequence of a neurochemically mediated (through dopamine and/or glutamate) synaptic
apoptosis that would compromise cell function and alter brain morphology without, however,
producing serious cell injury (and thus inducing glial reactions).
Although some authors have suggested that pharmacologic treatment suppresses the symptoms of
schizophrenia but does not alter the course of the illness or its potential progression,
others have suggested that antipsychotic drugs in fact ameliorate the pathophysiologic
process that causes psychotic symptoms and leads to clinical deterioration. Moreover,
maintenance treatment studies have demonstrated the prophylactic effect of antipsychotic
drugs in preventing relapse; treatment, then, may be responsible for mitigating the course
of the illness and producing more favorable outcomes.
Three lines of evidence suggest that the novel neurotransmitter Nitric Oxide (NO) play a
central role in pathophysiology of schizophrenia. First, schizophrenia-like syndromes can be
induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties.
Recent studies indicate that the behavioral and biochemical effects of PCP in rats are
blocked by Nitric Oxid synthase (NOS) inhibitors, suggesting that NO plays an important role
in the pharmacological effects of PCP. Second, Postmortem brain tissue obtained at autopsy
from schizophrenia and control demonstrate increased in NOS in the cerebellum and brainstem
of schizophrenic patients. Third, NO play a role in learning and memory, which severly
impaired in schizophrenia.
Minocycline is a second-generation tetracycline used in humans, which effectively crosses
the blood-brain barrier. Minocycline is commonly used by humans, because of its beneficial
ant-imicrobial and anti-inflammatory properties. In addition, it has remarkable
neuroprotective qualities in animal models of cerebral ischemia, traumatic brain injury, and
Huntington's and Parkinson's disease. The neuroprotective effect of Minocycline is
associated with marked inhibition of inducible NO synthase (iNOS), caspase 1 and caspase 3
expression, and p38 mitogen activated protein kinase (MAPK). Recently, it was found that
Minocycline also inhibits cytochrome c release and delays progression of amyotrophic lateral
sclerosis in mice.
Because Minocycline may inhibit members of the caspase family, the MAP kinase pathway and
NOS (which play central role in the neuroprotective effects of Minocycline in different
model of brain-disease), we would like to test the neuroprotective effect of Minocycline in
the early development (i.e.- at the first psychotic episode) of schizophrenia. The safety
record of Minocycline and its ability to penetrate the blood-brain barrier are well known.
Therefore, if this drug will be found to have neuroprotective effect in schizophrenia it may
be a novel therapy.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention