The International Journal of Psychosocial Rehabilitation
Effectiveness of Adjunctive Reboxetine
on Deficit Symptoms of Schizophrenia



Saeed Shoja Shafti (M.D)
Associate professor of Psychiatry
University of Social Welfare and Rehabilitation Sciences
(USWR)
Razi Psychiatric Hospital
Amin Abad – Shahre Rey
Tehran - Iran
E-mail: ssshafti@gmail.com
----------------------------------------------------------------------
Mohammad Sadeghe Jafarabad (M.D)
Psychiatrist
Razi Psychiatric Hospital
M_sjafarabad@yahoo.com
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Reza Azizi (M.D)
Razi Psychiatric Hospital
Re_azizi2@yahoo.com







Citation:
Shafti SS, Jafarabad MS & Azizi R (2014)  Effectiveness of Adjunctive Reboxetine on Deficit Symptoms
 of Schizophrenia
.  International Journal of Psychosocial Rehabilitation. Vol 18(2) 113-120





Abstract
Objective: Deficit syndrome is an important dilemma against social participation of schizophrenic patients. Reboxetine is a norepinephrine reuptake inhibitor (NRI) .Objective of this study was to evaluate its effect on the negative symptoms of schizophrenia.
Method: in a 12-week randomized placebo-controlled trial, reboxetine was compared with placebo, as an adjunctive to haloperidol (5 mg), for treatment of 50 patients meeting DSM-IV-TR criteria for schizophrenia. In this respect, Scale for Assessment of Negative Symptoms (SANS) was used as the primary outcome measure. Treatment efficacy was analyzed by t test, Split-plot (Mixed) and repeated –measures analysis of variance (ANOVA).
Result: The primary finding of this trial was a significant reduction in mean total scores of SANS in the reboxetine group, in comparison with the placebo group, at the end of the 12th week (P <0.0001). As well, in the experiment group, all of the sub-scales of SANS demonstrated considerable improvement. A trivial escalation in mean total scores of SAPS also was evident in the later group. Effect Size (ES) analysis too at the end of the trial, pointed to a large improvement with reboxetine.
Conclusion: reboxetine, as adjuvant to haloperidol, may cause a favorable outcome on behalf of improvement of deficit symptoms of schizophrenia.

Keywords: schizophrenia; negative symptom; reboxetine.



Introduction
Antidepressants have plenty and varied credentials as plausible therapeutic agents regarding negative symptoms of schizophrenia (David Taylor, et al, 2012). Although negative symptoms (Affective Blunting, Alogia, Avolition, Apathy, Anhedonia, Asociality and Attention Deficit) are not uncommon in schizophrenia, but nevertheless their management is not smooth. Moreover other questions exist incidentally. For instance, use of antidepressants in the presence of concomitant depression in schizophrenia raises this question that treatment is mostly an antidepressant effect and not a direct effect on negative symptoms.

Most of the trials of antidepressants in schizophrenia are add-on studies and placebo-controlled trials of antidepressants in non-depressed schizophrenic patients have not shown consistent results (Silver H,et al,1992). For example, whilst fluvoxamine and fluoxetine have shown efficacy over placebo in some trials (Goff DC,et al,1995), on the contrary, there are similar trials as well with citalopram and fluoxetine with negative outcome that make crucial judgment more complicated ( Carpenter W ,1997).
As another example, while a trial of amitriptyline in this regard showed positive results, but no significant effect with maprotiline in comparable assessment were visible. Antidepressants like mirtazapine and mianserin as well have been studied with encouraging results (Zoccali R, et al, 2004).

Reboxetine [2-[(2-ethoxyphenoxy)-phenyl-methyl]morpholine]    is an antidepressant drug used in the treatment of clinical depression, panic disorder and ADD/ADHD and  exists as two enantiomers, (R,R)-(-)- and (S,S)-(+)-reboxetine.14

Both the (R, R)-(-) and (S, S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.

 Reboxetine essentially acts as a pure norepinephrine reuptake inhibitor (NRI) with very little activity on the serotonin transporter and without direct effects on the dopaminergic neurotransmission (Weiss J, et al, 2003) and hence is a somewhat well-tolerated, fairly selective "noradrenergic" agent. NARIs may be especially useful in drive-deficient "anergic" states where the capacity for sustained motivation is lacking and also in the treatment of retarded and melancholic depressive states with a reduced capability to deal with stress20. Previous studies have shown contradictory results (Raedler TJ,et al,2004; Schutz G,et al,2003) concerning the helpful effects of reboxetine on deficit symptoms. Objective of this study includes exploration of the effectiveness of reboxetine, as an adjunctive treatment, in a group of schizophrenic inpatients with prominent negative symptoms.

Method
50 male inpatients meeting diagnosis of schizophrenia, according to the clinical interview and Diagnostic and Statistical Manual of Mental disorders (DSM-IV-TR) (Code: 295.xx) were entered, into a 12-week parallel group, double-blind study for random assignment to adjunctive reboxetine (n=25 patients) or placebo (n=25 patients).
Since the field of research was restricted to chronic male district of the psychiatric hospital therefore all of the samples were selected among chronic male schizophrenic patients. After complete description of the study to the subjects, written Informed consent was obtained from either the participant or a legal guardian or representative.  In addition whole of the procedure was approved by the related ethical committee of the university.

The inclusion criteria, in addition to the diagnosis of Schizophrenia, included the existence of apparent negative symptoms and duration of at least two years. Cases with Co-morbidities like Major Depressive Disorder, mental retardation, neurological disorders, medical complications, severe aggressiveness, medical deafness or muteness, were excluded from the study. In addition cases with diagnosis of Schizoaffective Disorder or cases that were prescribed atypical antipsychotics, antidepressants or lithium as well had been expelled.

High negative symptoms scores (more than 20% of total SANS, =or>24), low positive symptoms scores (less than 20% of total SAPS, =or<35), low extra-pyramidal symptoms scores (less than %25 of total SAS, =or<10), and finally low depressive symptoms scores (HDS less than 10) were at the base of our inclusion criteria.
To exclude depression and cognitive disturbances that could be confused with negative symptoms, Hamilton Depression Scale (HDS) and Mini-Mental Status Examination (MMSE) were used respectively. A HDS more than 10 and MMSE less than 25 were diagnosed as depression and cognitive disturbance and led to patient exclusion.
All patients, after a washout period of two weeks, subsequent to tapering of their previous typical antipsychotics (neither of them had received any form of Depot injection during the last six months before entering the study), were receiving daily haloperidol (5 mg/day). After that, they were randomized to placebo or reboxetine (4 mg daily) groups.

 Since higher dosages of Reboxetine, like other antidepressants, could increase the hazard of intensification of psychosis, and the aim of this study was assessing the efficacy of that drug on merely the negative symptoms of schizophrenia, not treating MDD (that needs usually 4-8mg/day reboxetine), therefore the lower dosage was selected in the current trial.

The tablets were prescribed while previously inserted into empty and similar capsules, which were prepared in this regard, to make patients blind with respect to the procedure. Evaluator [a psychiatrist] as well remained unaware concerning the abovementioned panel and the type of medications prescribed for each group.  All The patients remained hospitalized throughout the experiment.

Scale for Assessment of Negative Symptoms (SANS) was used as the primary outcome measure in this experiment for appraisal of Affective blunting (restricted emotional expression), Alogia (reduced spontaneous speaking), Avolition (lack of drives, Anhedonia (lack of sense of pleasure) and Attention deficit.
In addition Scale for Assessment of Positive Symptoms (SAPS), Simpson Angus Scale (SAS) and Hamilton Depression Scale (HDS) were used for comparison of the intervening parameters in this study. 

Duration of assessments was twelve weeks, and the patients were assessed at the beginning, as baseline, and at the end of the 4th, 8th and 12th week with regard to SANS and SAPS. All of the remaining scales had been scored at the initiation and conclusion of the experiment. Analysis of the Scores of SANS at 12th week was the core objective of this study.
It is mentionable that according to a Priori Power Analysis and based on a large effect size (according to Cohen's definition) along with an alpha=0.05; a total sample size of at least 42(2x21) could predict a power=%80 in this regard [Critical t (40) =1.68, delta=2.59, actual power=0.81].Given the high probability of dropouts, we increased the sample size to 2x25.

Statistical Analysis:
patients were compared on baseline characteristics using chi-square tests for categorical variables and t tests for continues variables in order to assess the efficacy of the randomization procedure in ensuring homogeneity between the two treatment groups.
The primary analysis was carried out according to the intention-to-treat, last- observation –carried-forward (LOCF) approach. Treatment efficacy was analyzed by t test, Split-plot (Mixed) and repeated –measures analysis of variance (ANOVA) comparing both groups over 12 weeks, with regard to SANS and SAPS. Cohen effect size estimates were used when comparing baseline to end-point changes in SANS. All tests of hypotheses were tested at a two-sided alpha level of 0.05. Response was defined as a reduction of 20% or more in the severity of SANS’s score (total and/or sub-scales).

Results
Analysis for efficacy was based on data from equal number of patients (n=25) in both groups, because there was no drop out throughout the assessment. It is mentionable that since all of the patients were hospitalized all over the study in the hospital and furthermore due to lack of serious adverse effects in them and besides short duration of experiment, hence there was no premature discontinuation in none of the aforesaid groups. Groups were originally analogous with respect to comparable demographic and diagnostic variables (Table1).

Table1- Baseline Demographic and Disorder Characteristics of the Participants.

Variables

Placebo 

Reboxetine

X2

t

df

p

CI

No of Schizophrenic patients

N=25       

N=25   

0.02

 

1

0.88

 

Age (yr/o)

4.21+/-84. 39

1.17+/-41.03

 

1.36

48

0.17

-0.56 to 2.94

Duration of illness(yr)

1.28+/-8.69

0.37+/-9.01

 

1.20

48

0.23

-0.21 to 0.85

No of Married patients.

N=18

N=15

0.12

 

1

0.72

 

No of Prior episodes: Mean+/-SD

9.29+/-2.14

8.93+/-1.72

 

0.65

48

0.51

-1.46 to 0.74

MMSE

27.41+/-1.38

26.68+/-1.59

 

1.73

48

0.08

-1.57 to 0.11

HDS

5.36     1.83+/-

 

1.69+/-6.02

 

1.32

48

0.19

-0.34 to 1.66

Baseline SANS

80.42+/- 2.46

79.94+/-1.20

 

0.877

48

0.384

-0.62 to 1.58

Baseline SAPS

85.27+/-6.13

86.36+/-7.15

 

0.579

48

0.565

-4.78 to 2.69

Abbreviations: MMSE = Mini-Mental Status Examination, HDS = Hamilton Depression Scale, SANS = Scale for Assessment of Negative Symptoms, SAPS = Scale for Assessment of Positive Symptoms.

The main outcome measures in this assessment were mean total changes of SANS and though at baseline there was no important difference regarding them between experiment and control groups, but at the end reboxetine illustrated significant improvements in the severity of negative symptoms (Table 2, 3).

Table2- Between-group analysis of Primary outcome Measures at Baseline, 4th, 8th and 12th week.

MEASURES\DRUGS

Reboxetine

placebo

t

df

P

CI

SANS- Baseline

79.94+/-1.20

80.42+/- 2.46

0.877

48

0.384

-0.62 to 1.58

SANS-4th week

78.73+/-5.62

80.59+/-4.81

1.257

48

0.214

-1.11 to 4.83

SANS- 8th week

76.04+/6.84

79.93+/-5.93

2.149

48

0.036

0.25 to 7.53

SANS-12th week

74.23+/-4.07

79.87+/-5.83

2.630

48

0.011

0.88 to 6.59

SAPS- Baseline

86.36+/-7.15

85.27+/-6.13

0.579

48

0.565

-4.78 to 2.69

SAPS-4th week

86.79+/-6.23

85.46+/-5.82

0.780

48

0.439

-4.75 to 2.09

SAPS- 8th week

87.61+/-4.69

85.19+/-4.58

1.84

48

0.071

-5.05 to 0.21

SAPS-12th week

88.69+/-7.41

85.31+/-7.59

1.59

48

0.117

-7.64 to 088


Table3 – Intra-group Analysis of Primary Outcome Measures between Baseline and 12th week.

Measures\weeks

Baseline

12th week

t

DF

P

CI

SANS-Reboxetine

79.94+/-1.20

74.23+/-4.07

6.728

48

0.0001

4.04 TO 7.41

SANS-placebo

80.42+/- 2.46

79.08+/-5.83

1.059

48

0.295

-3.88 to 1.20

SAPS-Reboxetine

86.36+/-7.15

88.69+/-7.41

1.131

48

0.263

-1.81 to 6.47

SAPS-placebo

85.27+/-6.13

85.31+/-7.59

0.020

48

0.983

-3.88 to 3.96

Abbreviations: SANS=Scale for Assessment of Negative Symptoms, SAPS=Scale for Assessment of Positive Symptoms.

Regarding to baseline and final mean total scores of SAPS, SAS and HDS also no significant difference was observable among them(Table 1, 2).

According to the findings and at the end of the assessment,76% of patients in the reboxetine  group, comparing to 24% of them in the control group, based on improvement in  SANS scores, demonstrated some positive response to this adjunctive augmentation , (x2 =5.760, DF=1,P=0.016) (Table4).

Table 4- Number of patients with significant improvement in total and subtests of Scale for Assesment of Negative Symptoms (SANS) in reboxetine group compared to placebo group.

Negative symptoms

Placebo

 (%)

 

Reboxetine (%)

Chi Square

DF

P value

Contingency

Coefficient

AB

(%4)1

8 (32%)

4.000

1

0.045

0.555

ALOGIA

(%12)3

12 (48%)

4.267

1

0.038

0.471

AA

(%8)2

10 (40%)

4.083

1

0.043

0.504

An As

(%4)1

9 (32%)

4.900

1

0.025

0.573

AD

(%8)2

11(44%)

4.923

1

0.026

0.524

total

6 (24%)

19 (76%)

5.760

1

0.016

0.433

Abbreviations: AB= Affecting Blunting; AA=Avolition-Apathy

In this regard, the SANS’s mean total score in the reboxetine group decreased from 79.94+/-1.20 to 74.23+/-4.07 (95%CI: 4.04 to 7.41, DF=48, t=6.728, P<0.0001) at the end of the study, while such an improvement was not manifest in the placebo group (80.42+/- 2.46to 79.08+/-5.83; 95%CI: -3.88 to 1.20, df=48, t=1.059, P=0.295) (Table3).
 Between-group analysis showed that the mean total scores of SANS in the reboxetine group , in comparison with the control group, improved significantly at 8th and 12th week (P<0.036 and P<0.011 respectively) (Table 2). 

Repeated-measures (within-subjects factor) analysis of variance (ANOVA), regarding the mean total scores of SANS, showed significant improvement in the reboxetine group [F (3, 72) = 3.25 p<0.026579 SS=591.95 MSe=60.66], along with non-significant change in the control group (F (3, 72) = 0.231 p<0.874429 SS=35.74 MSe=51.54).
Split-plot (Mixed, Between-within) design ANOVA also showed considerable difference in this regard among them [F (3, 96) = 4.11 p<0.0019768 SS=6.71 MSe=32.98].

Also regarding the mean total scores of SAPS, repeated-measures analysis of variance (ANOVA) illustrated non-significant alterations in the reboxetine and control groups [F(3,72) = 0.853 p<0.469600 SS=76.85 MSe=30.04 and F(3,72) = 0.009 p<0.998834 SS=0.83 MSe=31.00 respectively] and likewise Split-plot (Mixed) design ANOVA did not prove any considerable difference in this regard among them [F(3,96) = 0.397 p<0.755679 SS=35.56 MSe=29.88].

According to the results, all of the subscales of SANS demonstrated significant improvement in the reboxetine group vis--vis the placebo group (Table4).

Albeit no important altering in the positive, extra-pyramidal and depressive symptoms all through the present study was discernible, but it should be pointed out that nevertheless by means of this minor dosage of reboxetine the mean total scores of SAPS showed a trivial escalation in the experiment group (86.36+/-7.15to 88.69+/-7.41, 95%CI: -1.81 to 6.47, DF=48 t=1.131, P=0.263).

48% (n=12) of the patients in the placebo group and 40% (n=10) of them in the reboxetine group required anticholinergic drug for remission of the tremor or Parkinsonism at some stage in the study (Chi-Square=0.081, DF=1, P=0.77).

Since the sample size was small, hence the Effect size (ES) was analyzed for change on the SANS at the end of treatment, which indicated a large (   " d = or >0 .8"), readily observable improvement with reboxetine (Cohen's d = 2.91, effect-size r = 0.82).

Nine patients in the reboxetine group (36%) experienced some mild to moderate side effects such as headache, insomnia, constipation and dry mouth but neither of them led to any major problem or withdrawal from the experiment.

Discussion
According to the assessments, reboxetine, as an adjuvant agent, induced notable improvement in the negative symptoms, while in the meantime it caused not important increase in the positive syptoms.

 As is known, reboxetin is helpful in treatment of depression (David Taylor, et al, 2012). It also reduces olanzapine-associated weight-gain through activation of the adrenergic system (Poyurovsky.M, et al, 2003). As is known, the dopamine-blocking properties of antipsychotic drugs may have a negative effect on mood and drive and, in addition, treatment with typical antipsychotics has been associated with emergence of depression in schizophrenia (David Taylor, et al, 2012).

There is evidence that NARIs indirectly enhance central serotonin function by a mechanism that doesn't depend on reuptake inhibition. An association between negative symptoms and dysregulation of the serotonin system is suggested by an abnormal prolactin response to fenfluramine in schizophrenia and schizoaffective disorder (David Taylor, et al, 2012).  On the other hand, reboxetine also has a modulating effect on the dopaminergic cells in the ventral tegmental area and may cause a selective increase in the dopamine availability in the prefrontal cortex. Thus it may possibly help to undo a number of challenging side effects of antipsychotics on mood and drive ( Poyurovsky.M,et al,2003).

In a comparative study, reboxetine was considerably better than paroxetine and placebo regarding improvement of attention and enhancement of cognitive functioning in patients suffering from MDD (Raedler TJ,et al,2004) ; an outcome that persuades comparable survey respecting schizophrenic patients.

In a six-week randomized controlled trial on 30 schizophrenic patients, there was no significant difference among reboxetine and placebo on the topic of improvement of deficit symptoms (Schutz G,et al,2003). conversely, in an open-label trial for seeking the effectiveness and tolerability of the adjunctive reboxetine in a group of schizophrenic patients  with prominent depressive or negative symptoms, all clinical scores  improved significantly as a result of adjunctive treatment with reboxetine  (Raedler TJ,et al,2004).   In addition all of the patients tolerated treatment without any major adverse effects. The results of the present study are in agreement with the later study.  Also, the short period of this assessment and lesser dosage of reboxetine prescribed in that may possibly have held the efficiency of reboxetine in low esteem. Also whether addition of reboxetine to atypical antipsychotics could result in the same outcome or not, needs its appropriate evaluation.Even though these results are investigative and have to to be confirmed by further analogous studies but nonetheless they were encouraging, since they have illustrated a consequential amelioration of negative symptoms in a group of schizophrenic patients. Small sample size and short duration of experiment were among the major limitations of this assessment.

Conclusion:
Reboxetine, as adjuvant to haloperidol, may cause a favorable outcome on behalf of improvement of deficit symptoms of schizophrenia.



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