Authored by Saeed Shoja Shafti
Abstract
Objective: Problem with memory and attention is a neglected
aspect of schizophrenia. The most affected domains are attention,
working
memory and semantic memory. The impairments are, like the negative
symptoms, basically stable and independent of the positive symptoms.
Since
such deficits do not respond to antipsychotics, during the past years
some approaches have been done by different acetylcholinesterase
inhibitors.
Assessment of the effectiveness of rivastigmine, as an add-on therapy,
on clinical symptoms of schizophrenia, was the main objective of the
present
study.
Methods: 46 male inpatients, with diagnosis of schizophrenia,
entered a 12-week, double-blind, clinical trial for random assignment to
placebo
or rivastigmine, as adjuvant to their current antipsychotic medication.
‘Positive and Negative Symptom Scale (PANSS)’ and ‘Mini Mental State
Examination (MMSE)’ had been used as the main outcome scales. ‘Clinical
Global Impressions- Global Improvement (CGI-I)’ and ‘Extrapyramidal
Symptom Rating Scale (ESRS)’ had been used as the ancillary scales.
Results: According to the findings, except than significant
enhancement of MMSE by rivastigmine (p<0.001), no significant
improvement
in positive, negative and general psychopathology of schizophrenia was
evident in the target and control groups. Also, except than significant
enhancement of CGI-I by rivastigmine in intra-group analysis, no
significant improvement was apparent in between- group analysis. ESRS,
too,
did not display any significant alteration in either group. Finally,
effect size (ES) analysis exhibited a large improvement of MMSE by means
of
rivastigmine.
Conclusion: Disregard to positive or negative symptoms,
rivastigmine can significantly improve the cognitive function of
schizophrenic patients,
which may be favorable for psychosocial intervention or rehabilitation
of this group of patients.
While around 0.3-0.7% of people suffer from schizophrenia
at some point in their lifetime [1], it causes approximately 1% of
worldwide disability [2]. In 2000, the World Health Organization
declared that the incidence and prevalence of schizophrenia is
approximately comparable around the world, with age- standardized
prevalence per 100,000 populations ranging from 343 in Africa to
544 in Japan and Oceania for men [3]. Schizophrenia is a mental
disorder, which is usually characterized by strange social behavior
and lack of insight. Its diverse clinical features have caused a doubt
that whether such a diagnosis characterizes a solitary disorder or a
collection of separate syndromes [4].
In addition, the mean life expectancy of persons suffering from
this illness is 10 to 25 years lesser than the mean life expectancy
of people without that problem [5]. Perhaps, this is due to higher
risk of suicide and missed somatic complications among this group
of patients [6]. Besides, problems in short-term and long-term
memory, disturbed social communication, and unemployment, are
the common complications of schizophrenia [7,8]. Recently, lots
of efforts have been done to recognize and manage the prodromal
phase of schizophrenia, which may be identified about thirty
months in advance of overt psychosis [9]. While specific care has
been paid to the role of dopamine in the mesolimbic circuit of the
brain, the dopamine theory is now supposed to be imperfect [10].
Specific attention, also, has been paid to the role of glutamate
and its receptor in schizophrenia, mostly due to abnormal levels of
glutamate receptors that has been found in the postmortem brains
of schizophrenic patients [11], and the finding that glutamateblocking
drugs such as ketamine and phencyclidine may simulate
the signs and symptoms of schizophrenia [12]. While antipsychotic
drugs remain the basis of management for schizophrenia, the search
is now planned for medications that may improve the cognitive
problems and negative symptoms of schizophrenic patients. As is
known, acetylcholinesterase inhibitors (AChEIs) have long been in
use for management of cognitive symptoms of dementia [13].
On the other hand, cognitive problems have been designated in
schizophrenic patients from the first reports of dementia praecox
up to present-day conceptions of cognitive disorders. Nonetheless,
a little is known about how to manage them. While in Alzheimer
disease, cholinergic deficit has been found and cholinesterase
inhibitors have been utilized to interrupt the progress of memory
and cognitive dysfunction, the existing evidence suggests that
the cholinergic system may be disordered in schizophrenia, too
[14]. It means that, in patients with schizophrenia, changes such
as decreased nicotinic and muscarinic receptors in the central
cholinergic system may contribute to these cognitive deficiencies.
Since such shortages do not usually respond to available
neuroleptics, different pharmacological treatments have been
developed for enhancement of central cholinergic transmission, for
instance with AChEIs [15].
Donepezil, rivastigmine, and galantamine, are cholinesterase
inhibitors used to treat mild to moderate cognitive impairment
in dementia of the Alzheimer’s type [16]. In this regard, cortical
acetylcholine (ACh) diminution, as well, has been suggested to
relate to psychotic symptoms like visual hallucinations and the
amount of diminution is said to be associated with the harshness
of the symptoms. Some data proposes that AChEIs may show
useful in controlling of visual hallucinations [17]. As augmentative
agents, while according to some studies, cholinesterase inhibitors
have shown useful influences respecting enhancement of
cognitive function [18] or improvement of psychotic symptoms of
schizophrenic patients [16], contradictory or unsuccessful trials
are existent in this regard [15,19].
Rivastigmine is a parasympathomimetic or cholinergic agent
and can be prescribed orally or via a transdermal patch; the
latter method decreases the frequency of adverse effects, which
usually involve nausea and vomiting. The drug is eliminated
through the urine and seems to have few drug-drug interactions
[20]. Rivastigmine has shown treatment effects on the cognitive,
functional, and behavioral problems commonly associated with
Parkinson’s and Alzheimer’s disease dementias [21]. Particularly,
it seems to demonstrate noticeable therapeutic effects in patients
suffering from a more violent course of disease, such as those
with younger age of onset, unfortunate dietary situation, or those
experiencing psychotic symptoms [21].
For instance, the existence of hallucinations appears to be a
predictor of particularly strong response to rivastigmine in both
of Parkinson’s and Alzheimer’s patients [22]. These effects might
reflect the advantageous effect of additional inhibition of butyryl
cholinesterase by rivastigmine [22]. The aim of the present appraisal
included evaluation of the safety and clinical effects of rivastigmine,
as an adjunctive medication in accompany with antipsychotic drug,
in patients with schizophrenia.
46 male inpatients with diagnosis of schizophrenia, according
to the Diagnostic and Statistical Manual of Mental Disorders, 5th
edition [23], after complete description of the method and obtaining
signed informed consent, entered into one of the designated groups,
for random assignment to placebo or rivastigmine, as adjuvant
to their current antipsychotic medication, which included one of
the conventional antipsychotics like chlorpromazine, haloperidol,
trifluoperazine and perphenazine. All samples had been identified
as schizophrenia from at least two years ago.
Exclusion criteria in the existing valuation consisted: Any comorbid
or another mental disorder in axis I except for schizophrenia,
documented neurological or medical ailment, consumption of
depot antipsychotics, or concurrent medicines like antidepressants
or mood stabilizers. Similarly, no other psycho-social mediation or
psychotropic medication, throughout the survey, was allowable.
Due to possible advantages of atypical antipsychotics on cognitive,
depressive and negative symptoms of schizophrenia, from one
hand, and definitively fewer extra-pyramidal adverse effects by
them, on the other hand, so their consumption, as well, had been
included as exclusion criteria in the present assessment [24].
Because the field of study was limited to chronic male ward
of the hospital, therefore all samples had been chosen among the
accessible male inpatients. While the evaluation had been done
according to a double-blind design, separation of patients into
groups was accomplished based on the number of beds, with odd
numbers into target group and even numbers into control group.
Evaluator (a skilled psychiatrist), staff and patients, were unaware
as regards the prescribed medications, which were filled into
similar capsules. Rivastigmine was started at a dosage of 3mg/day
in the 1st week, with bi-weekly increment of 3mg/day up to 12mg
in the 6th week, and then this dosage was held unbroken up to the
end of the assessment.
‘Positive and Negative Symptom Scale (PANSS)’ [25] and
‘Mini Mental State Examination (MMSE)’ [26] had been used as
the main outcome scales. ‘Clinical Global Impressions- Global
Improvement (CGI-I)’ [27] and ‘Extrapyramidal Symptom Rating
Scale (ESRS)’ [28] had been used as the ancillary scales. The length
of the appraisal was twelve weeks, and the cases were evaluated
by PANSS, MMSE, CGI-I and ESRS at baseline (week 0), and weeks
6 and 12. Adverse effects of drugs had been examined by another
associate psychiatrist at weekly visits or based on the staffs’ report.
Samples were matched regarding baseline characteristics by
t tests. Treatment effectiveness, as well, was evaluated by ‘t test’
and ‘repeated-measures analysis of variance (ANOVA)’ comparing
both groups over twelve weeks. Statistical significance was defined
as a 2 -sided p value < or = to 0.05. With regard to the significant
changes, ‘Cohen’s Standard (d)’ and ‘Correlation measures of effect
size (r)’ had been calculated for comparing baseline to end-point
alterations. MedCalc Statistical Software version 15.2 was used as
statistical software tool for analysis.
Groups were principally analogous and demographic and
diagnostic variables were comparable (Table1). Also, analysis for
effectiveness was based on data from identical quantity of samples
in both groups. 5 patients in the target group, due to reluctance
(n=2) or gastrointestinal problems (n=3), and 5 patients in the
control group, due to digestive complications (n=2) or reluctance
(n=3) left the study. In keeping with the findings and intra-group
analysis, and in comparison, with the starting point, no significant
improvement in mean total scores of PANSS was evident as regards
the positive, negative and general psychopathology in either group
(p<0.18, p<0. 44, p<0. 53 and p<0. 24, p<0. 49, p<0. 71, in the target
and control groups, respectively) (Table 2) (Figure 1,2).
Table 1: Demographic and Clinical Characteristics of Participants.
Table 2: Intra-group Analysis of Different Outcome Measures between Baseline and Week 12.
Repeated measure analysis of variance (ANOVA)’, as well, could
not display any significant alteration regarding the abovementioned
evaluations in both groups [F(2,51) = 0.815 p<0.44 SS=6.04
MSe=3.70, F(2,51) = 0.663 p<0.51 SS=13.48 MSe=10.17, F(2,51)
= 1.34 p<0.27 SS=104.15 MSe=39.01 & F(2,51) = 0.668 p<0.51
SS=4.59 MSe=3.44, F(2,51) = 0.833 p<0.44 SS=19.70 MSe=11.83,
F(2,51) = 1.30 p<0.28 SS=125.04 MSe=48.12, respectively].
Moreover, between-group analysis could not prove any important
difference between target group and control group concerning the
aforesaid comparisons (Table 3). But with respect to MMSE, though
a significant enhancement was evident in the target group at the
end of the assessment (p<0.001), no important improvement was
observable in the control group (p<0. 92) (Table 2,3) (Figure 3).
‘Repeated measure analysis of variance (ANOVA)’, too, indicated a
significant upgrading in the target group [F (2, 51) = 4.22 p<0.02
SS= 20.26 MSe= 2.40] and insignificant change in the control group
[F (2, 51) = 1.67 p<0.19 SS=32.15 MSe=9.62]. Similarly, betweengroup
analysis had shown a significant difference between
rivastigmine and placeo regarding improvement of MMSE at week
12 (p<0.0001), which was manifest from the sixth week (p<0.009)
(Table 3). Additionally, ‘split-plot (mixed) design ANOVA’ exposed
the significant influence of rivastigmine as opposed to placebo on
MMSE [F (4,153) = 3.89 p<0.004 SS=613.80 MSe=39.48].
Table 3: Between-Group Analysis of Different Outcome Masseurs in Weeks 0, 6 and 12.
Regarding CGI-I, though according to intra-group analysis a
significant progress was obvious in the target group (p<0. 05)
(Table 2), it was not similarly significant in between-group analysis
(0.09) (Table 3). In this regard, ‘split-plot (mixed) design ANOVA’, as
well, did not show any important difference between rivastigmine
and placebo [F (4,153) = 11.7 p<0.08 SS=420.73 MSe=8.98]. In
connection with ESRS, intra-group and between-group analysis did
not illustrate any significant alteration in either group. Since the
sample size was small, the effect size (ES) was analyzed for changes
in MMSE and CGI- I, at the end of evaluation, which indicated a
large (d = 0.8 or r= 0.73) and nearly medium (d = 0.5 or r= 0.24)
improvement by rivastigmine (1.18 & 0.50 and ; 0.66 & 0.31, as
‘Cohen’s d’ and ‘effect- size correlation r’, respectively).
‘Post hoc’ power analysis presented an intermediate’ power
=0. 43’ for this assessment, which turned to ‘power =0. 77’ as
‘compromise power analysis’. The most common side effects of
rivastigmine in the current study were vomiting (n=1), nausea
(n= 2), diarrhea (n=1), and dizziness (n=1). The adverse effects
in the control group also were vomiting (n=1), nausea (n=1), and
dizziness (n=1). ‘Comparison of proportions’ did not show any
significant difference between two groups regarding the occurrence
of adversative effects (z=0.80, p=0.42, CI 95%= -0.38, 0.16).
Schizophrenia is a main reason of incapacity and is classified
as the third-most- disabling illness subsequent to dementia and
quadriplegia, and ahead of blindness and paraplegia [29]. Nearly,
75% of persons with schizophrenia have continuing problems
with recurrent psychotic episodes [30]. While antipsychotics are
known as the principal treatment for schizophrenia [31-33], they
cannot usually improve the cognitive dysfunction and negative
symptoms [8-34]. Problem with memory and attention is generally
an ignored aspect of schizophrenia. The most affected domains are
attention, working memory and semantic memory. These deficits
are superimposed on a generalized intellectual deficit averaging
about one standard deviation [35]. According to some studies on
patients at risk for schizophrenia, such as first-degree relatives
and individuals with schizotypal personality disorders, and, also,
first-episode patients, information processing deficits are among
the earliest clinical or cognitive markers of vulnerability for
schizophrenia [36].
Rivastigmine inhibits both butyryl cholinesterase and
acetylcholinesterase, unlike donepezil, which selectively inhibits
acetylcholinesterase. It is supposed to work by inhibiting these
cholinesterase enzymes, which would otherwise break down the
brain neurotransmitter acetylcholine [37]. As a semi-synthetic
derivative of physostigmine, it has been accessible in capsule and
liquid formulations since 1997 [38]. In 2006, rivastigmine came
to be the first product approved worldwide for the management
of mild to moderate dementia associated with Parkinson’s disease
[20]; and then in 2007 its transdermal patch became the first patch
treatment for dementia [38].
Evaluation of the efficacy and safety of rivastigmine, as an
adjuvant to current antipsychotic treatment in schizophrenic
patients, was the main objective of the present assessment.
Consistent with the findings, though rivastigmine did not display
any significant effect regarding amelioration of positive and
negative symptoms and general psychopathology of schizophrenia,
it could significantly improve the cognitive capacity of patients in
the related group, which was marked in the second half of the study.
Consequently, about intellectual function, our finding was in accord
with the results of [13,18], and in contrast to [15,19].
Such a conclusion may be favorable for enhancement of
outcome of psychosocial intervention or rehabilitation of this
group of patients, which demands another methodical research for
measurement of the pertained functional parameters. As regards
the positive symptoms, though the present assessment could not
find any valuable effect, Sachin et al. in their review of literature,
had found advantageous effects by AChEIs for the management of
visual hallucinations in schizophrenia [17], an important finding
that demands more systematic studies. Incidentally, it should be
mentioned that visual hallucinations are a well-recognized and stressful symptom in a range of psychiatric syndromes including
schizophrenia.
Visual hallucinations occur, as well, in several neurological
illnesses, but are most noticeable in Lewy body dementia, Alzheimer
disease and dementia due to Parkinson’s disease. While the lifetime
prevalence of visual hallucinations in patients with schizophrenia
is believed to be more common than what was usually thought,
its frequency ranges between 24%-72% [39-40]. Though both
dopaminergic and cholinergic perturbation have been linked with
visual hallucinations, neither of these offers an etiological model. It
is suggested that ‘acetylcholine in the human brain may modulate
the interaction between bottom-up and top-down processing in
determining proper neural representations for perceptual inputs’
[41].
According to this theory, while low levels of cortical
acetylcholine would result in the increased salience of top-down
information, high levels would result in over-processing of bottomup
stimulus driven information. Considering present concept of the
role of cholinergic system in visual pathways and the suggestion
that maybe AChEIs are of use in treating visual hallucinations in
the abovementioned circumstances, it would appear possible
that they may likewise be useful in schizophrenia-related visual
hallucinations [17].
On the other hand, Singh et al. [13] had found that the
acetylcholinesterase inhibitor plus antipsychotic had displayed
profit over antipsychotic and placebo in PANSS negative symptoms,
PANSS general psychopathology, along with cognitive function,
and the outcomes looked to favor the use of AChEIs , as adjuvant
to antipsychotic, on some spheres of cognition and mental state,
though due of numerous limitations in the studies the evidence
was not strong enough [13]; A finding that was not verifiable in
the present appraisal as regards negative symptoms and general
psychopathology of schizophrenia. Instead, while in our estimation
the CGI-I of the target group had revealed some significant progress
in the intra-group analysis, comparing starting point with end
point, it was not significant in between-group analysis and repeated
measure analysis of variance.
So, a practical conclusion is not presently possible. Friedman,
also, had proposed that, based on the existing studies, specific
cognitive deficits (like memory and attention) of patients with
schizophrenia and schizoaffective disorder are responsive to
AChEIs, as add-on therapies. So, he had suggested that whereas
a cholinergic approach to ameliorating the cognitive dysfunction
of schizophrenia seems worthwhile, there is some preliminary
information to support the usefulness of joined acetylcholinesterase
inhibitors and allosteric potentiators of the nicotinic receptor [18].
Lenzi et al, also, in an open study found that rivastigmine treatment
could result in significant improvements in quality of life, cognitive
function, learning, memory, attention, and finally “anergia” in Brief
Psychiatric Rating Scale (BPRS) [42].
But in contrast, Sharma et al. [19] in a 24-week randomized,
placebo-controlled, double-blind study could not find any significant
enhancement in any cognitive measurement by rivastigmine. As
stated by him, ‘while some cognitive variables exhibited noteworthy
alterations in both the placebo and rivastigmine groups, no
significant effects were discernible in clinical symptoms or side
effects profiles’ [19]. Similarly, Voss et al. had concluded that ‘thus
far randomized, placebo-controlled studies are existent only for
rivastigmine and donepezil, and none could reproduce the positive
results of earlier appraisals with open designs’; an attitude similar
to [43-46], and in conflict with our inference.
While the most common adverse effects of rivastigmine are
diarrhea, nausea, vomiting, dizziness, anorexia, weight loss, fatigue,
headache, abdominal pain, and somnolence [16], only the first
four were evident in our trial. Consistent with literature, since
rivastigmine has virtually no potential for interaction, because
it is metabolized at the site of action and does not affect hepatic
cytochromes [47], it seems to be least possible to cause challenging
drug interactions, an issue that can be vital in an elderly population
subject to polypharmacy [47].
Nevertheless, worries regarding the potential cardiac adverse
effects connected with AChEIs have been upraised subsequent to
outcomes from controlled trials of galantamine in mild cognitive
impairment (MCI), in which increased mortality was correlated to
galantamine [48]. While no definite cause of death was predominant,
half the expiries were reported as a result of cardiovascular
disorder. So, FDA issued a warning to restrict galantamine in
patients with MCI. Anyhow, its relevance to Alzheimer’s disease
remains indistinct [49]. In this regard, a population-based study
using a case-time-control design examined health records for 1.4
million older adults in Ontario and found that treatment with
AChEIs was associated with doubling the risk of hospitalization
due to bradycardia [49]. Regarding the cognitive measurement in
the present assessment, it deserves to be mentioned that while the
MMSE is one of the best-known cognitive assessment scales in the
mental health field, it has limited utility in those with schizophrenia.
The MMSE was developed for those with organic disorders (such
as dementia) who tend to have difficulties with orientation and
language. Indeed, people with schizophrenia rated with the MMSE
frequently obtain scores within the normal range.
So, maybe other fresher measure like ‘Brief Assessment of
Cognition in Schizophrenia (BACS)’, with greater validity and
reliability in people with schizophrenia would be a more reasonable
choice [49]. Short duration of study, small sample size, and genderbased
sampling were among the weak points of the present
evaluation. Further methodical studies with large samples, in
accompany with inclusive assessment of functioning and disability,
are required to determine the clinical usefulness of this treatment
approach.
Disregard to positive or negative symptoms, rivastigmine
can significantly improve the cognitive function of schizophrenic
patients, which may be favorable for psychosocial intervention or
rehabilitation of this group of patients.
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