Journal of Alcoholism Drug Abuse & Substance Dependence Category: Medical Type: Research Article
Challenging Deficit Syndrome of Schizophrenia by Norepinephrine Reuptake Inhibitor: A Controlled Clinical Trial
- Saeed Shoja Shafti1*, Mohammad Sadeghe Jafarabad2, Reza Azizi3
- 1 Professor Of Psychiatry, University Of Social Welfare And Rehabilitation Sciences (USWR), Razi Psychiatric Hospital, Iran, Islamic Republic Of
- 2 Psychiatrist, Razi Psychiatric Hospital, Iran, Islamic Republic Of
- 3 General Physician, Razi Psychiatric Hospital, Iran, Islamic Republic Of
*Corresponding Author:
Saeed Shoja ShaftiProfessor Of Psychiatry, University Of Social Welfare And Rehabilitation Sciences (USWR), Razi Psychiatric Hospital, Iran, Islamic Republic Of
Tel:+9821 3340122029,
Fax:+982133401604
Email:ssshafti@gmail.com
Received Date: Apr 24, 2019 Accepted Date: May 27, 2019 Published Date: Jun 04, 2019
Abstract
Despite advances made in treating the positive symptoms of schizophrenia, treatment of negative symptoms remains an unmet therapeutic need. 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 twelve-week randomized placebo-controlled trial, reboxetine was compared with placebo, as an add-on medication to haloperidol (5 mg), for treatment of 50 patients meeting diagnosis of schizophrenia. In this respect, Scale for Assessment of Negative Symptoms 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
INTRODUCTION
As another example, while a trial of amitriptyline in this regard showed positive results[9], but no significant effect with maprotiline in comparable assessment were visible [10]. Antidepressants like mirtazapine and mianserin as well have been studied with encouraging results [11-13]. 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 [15]. 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 [16] 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 stress. Previous studies have shown contradictory results [17-20] 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
STATISTICAL ANALYSIS
RESULTS
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.


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 |
2 7 .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 |
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 |
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 |
Negative symptoms |
Placebo (%) |
Reboxetine (%) |
Chi Square |
DF |
P value |
Contingency |
AB |
(%4)1 |
8 (32%) |
4.000 |
1 |
0. 045 |
0.555 |
ALOGIA |
(%12)3 |
12 (48%) |
4.267 |
1 |
0.0 38 |
0.471 |
AA |
(%8)2 |
10 (40%) |
4.083 |
1 |
0. 043 |
0.504 |
An As |
(%4)1 |
9 (32%) |
4.900 |
1 |
0.0 25 |
0.573 |
AD |
(%8)2 |
11(44%) |
4.923 |
1 |
0.0 26 |
0.524 |
total |
6 (24%) |
19 (76%) |
5.760 |
1 |
0.0 16 |
0.433 |
DISCUSSION
CONCLUSION
REFERENCES
- Evins AE, Goff DC. (1996) Adjunctive antidepressant drug therapies in the treatment of negative symptoms of schizophrenia. CNS Drugs. 6:130-147.
- Goff DC, Evins AE. (1998) Negative symptoms in schizophrenia: Neurobiological models and treatment response. Harvard Rev Psychiatry. 6: 59-77.
- Micallef J, Fakra E, Blin O. (2006) Use of antidepressant drugs in schizophrenic patients with depression. Encephale. 32: 263-269.
- Silver H, Nassar A, (1992) Fluvoxamine improves negative symptoms in treated chronic schizophrenia: an add-on double-blind, placebo-controlled study. Biol Psychiatry. 31:698-704.
- Spina E, De Domenico P, Ruello C. (1994 ) Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol. 9: 281-285.
- Goff DC, Midha KK, Sarid-Segal O, Hubbard JW, Amico E. (1995) A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology. 117: 417-423.
- Salokangas RKR, Saarijarvi S, Taiminen T. (1996) Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study. Acta Psychiatr Scand. 94: 175-180.
- Carpenter W. (1997) Pharmacotherapy of schizophrenia, Negative symptoms. (Sup) Am J Psychiatr. 154:123.
- Collins AD, Dundas J. (1967) A double-blind trial of amitriptyline/perphenazine, perhenazine and placebo in chronic withdrawn inert schizophrenics. Br J Psychiatry. 113: 1425-1429.
- Yamagami S, Soejima K. (1989) Effect of maprotiline combined with conventional neuroleptics against negative symptoms of chronic schizophrenia. Drugs Exp Clin Res. 4: 171-176.
- Berk M, Ichim C, Brook S. (2001) Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Int clin psychopharmacol. 16: 87-92.
- Zoccali R, Muscatello MR, Cedro C, Neri P, La Torre D, et al. (2004) The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol. 19: 71-76.
- Mizuki Y, Kajimura N, Imai T, Suetsugi M, Kai S, et al. (1990) Effects of mianserin on negative symptoms in schizophrenia. Int Clin Psychopharmacol. 5: 83-95.
- Fleishaker JC. (2000) Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clinical Pharmacokinetics. 39: 413–27.
- Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, et al. (2003) Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther.305(1): 197–204.
- Wong EH, Sonders MS, Amara SG, Tinholt PM, Piercey MF, et al. (2000) Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry. 47: 818–829.
- Schutz G, Berk M. (2001) Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: a preliminary double-blind randomized placebo-controlled study. Int Clin Psychopharmacol. 16: 275-278.
- Raedler TJ, Jahn H, Arlt J, Kiefer F, Schick M, et al. (2004) Adjunctive use of reboxetine in schizophrenia. Eur Psychiatry.19: 366-369.
- First MB, Spitzer RL, Gibbon M, Williams JBW. (1994) Structured clinical interview of axis-I DSM-IV disorders—patient edition (SCID-I/P, version 2.0). New York: Biometric Research Department, New York State Psychiatric Institute.
- Sadock BJ, Sadock VA. (2003) Kaplan & Sadock synopsis of psychiatry: Behavioral Sciences/Clinical Psychiatry. Ninth Ed. Philadelphia, PA, Lippincott Williams & Wilkins. 288.
- Massana J, Moller HJ, Burrows GD, Montenegro RM. (1999) Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder. Int Clin Psychopharmacol. 14: 73–80.
- Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, et al. (2003) Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry. 160: 297–302.
- Siris SG. (2000) Depression in schizophrenia: perspective in the era of “Atypical” antipsychotic agents. Am J Psychiatry 157: 1379–1389.
- Sharma RP, Singh V, Janicak PG. (1999) The prolactin response to fenfluramine in schizophrenia is associated with negative symptoms. Schizophr Res. 39: 85-89.
- Linner L, Endersz H, Ohman D, Bengtsson F, Schalling M, et al. (2001) Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex. J Pharmacol Exp Ther. 297: 540–546.
- Ferguson JM, Wesnes KA, Schwartz GE. (2003) Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients. Int Clin Psychopharmacol.18: 9-14.
Citation: Shafti ss, Jafarabad MS, Azizi R (2019) Challenging Deficit Syndrome of Schizophrenia by Norepinephrine Reuptake Inhibitor: A Controlled Clinical Trial. J Alcohol Drug Depend Subst Abus 5: 010.
Copyright: © 2019 Saeed Shoja Shafti, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
