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Sertraline as an add-on treatment for depression symptoms in stable

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Original article Sertraline as an add-on treatment for depression

symptoms in stable schizophrenia: A double-blind
randomized controlled trial
Victoria Omranifard1, Ghadir Mohammad Hosseini2, Mohammad Reza Sharbafchi2,
3 4 5
Mohammad Maracy , Fatemeh Ghasemi , Mahin Aminoroaia

1
Associate Professor, Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2
Resident of Psychiatry, Department of Psychiatry, Behavioral Sciences Research Center, School of Medicine And Student Re-
search Committee, Isfahan University of Medical Sciences, Isfahan, Iran
3
Associate Professor, Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
4
Clinical Psychologist, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
5
Researcher, Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
.

BACKGROUND: There have been few studies to specifically examine the efficacy of selective serotonin reuptake inhibitors
(SSRIs) for the symptoms of depression in schizophrenia. This study aimed to determine the efficacy of sertraline as a treatment for
depressive symptoms in patients with stable schizophrenia. METHODS: A 12-week randomized, double-blind, placebo-controlled
clinical trial was designed in 2010 with an active medication (sertraline) and a matching placebo. Sertraline was administrated 50-
200 mg/daily. A total number of 60 patients were randomized into two groups in a 1:1 fashion. Calgary Depression Scale for Schi-
zophrenia (CDSS) was used as the primary measure and Global Assessment of Functioning (GAF) scale was used as the secondary
measure. The data was analyzed by repeated measures analysis of variance (ANOVA) model to determine the effectiveness of sertra-
line. RSULTS: After 12 weeks, sertraline was significantly more effective than placebo in improving depressive symptoms in stable
schizophrenia (p = 0.003). The mean score of GAF did not differ significantly in the sample population as a whole (p = 0.093). The
difference between the two groups was not significant, either (p = 0.453). In addition, the rate of side effects was little but it was sig-
nificantly more in the sertraline group (p < 0.001). CONCLUSIONS: The results of this study suggested sertraline to be useful as a
treatment for depressive symptoms in patients with stable schizophrenia.
KEYWORDS: Sertraline; Schizophrenia; Post-Psychotic Depressive Disorder of Schizophrenia; Subsyndromal Depressive Symp-
toms; Negative Symptoms.

INTRODUCTION that  some  investigators  have  argued  that  de‐

pression is a core component of schizophrenia, sim‐
While  schizophrenia  and  depression  have  histori‐ ilar  to  positive,  negative,  and  disorganized  symp‐
cally been regarded as separate disorders, it is now  tom clusters [4].  
well  recognized  that  depressive  symptoms  are   
common in schizophrenia  [1]. It has been noted that  These  persistent  (or  emergent)  depressive  symp‐
most depressive symptoms occur concurrently with  toms  may  be  particularly  important  in  the  post‐
the acute psychotic symptoms, and resolve once an‐ psychotic period, as they have been associated with 
tipsychotic  treatment  is  implemented  and  the  psy‐ an  increased  risk  of  relapse  [5],  suicidality  [6],  and 
chosis  remits  [2].  However,  there  are  patients  with  impaired  social  and  vocational  functioning  [7].  And 
schizophrenia who experience persistent depressive  so  in  the  chronic  course  of  schizophrenia,  depres‐
symptoms  that  are  not  responsive  to  antipsychotic  sive  symptoms  appear  to  be  negative  prognostic 
treatment alone.   indicators  [7],  in  such  a  way  that  Changes  in  the 
  quality of life of schizophrenic patients is inversely 
Clinical entity, defined as post‐psychotic depressive  related  to  changes  in  the  concurrent  mood  disrup‐
disorder of schizophrenia according to the DSM‐IV‐ tion and early therapeutic interventions directed at 
TR criteria, is quite important in terms of follow up  a broader constellation of schizophrenic symptoma‐
procedures,  prognosis  and  determination  of  the  tology, including mood, may be helpful in improv‐
treatment  strategy  in  schizophrenic  patient.  In  the  ing an individual patientʹs quality of life [8]. 
other hand clinically meaningful subsyndromal de‐  
pressive  symptoms  have  been  reported  to  be  more  We  believe  that  the  early  recognition  and  proper 
prevalent  than  full  depressive  episodes  in  this  pa‐ treatment  of  this  relatively  common  depressive 
tient  population  [3].  Indeed,  they  are  so  prevalent   state  observed  to  arise  during  the  treatment  of 
Address of correspondence: Mohammad Reza Sharbafchi,  Resident of Psychiatry, Department of Psychiatry, Behavioral Sciences Research Center And
Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran. Email: sharbafchi@yahoo.com
Received: 20-11-2011; Revised: 03-12-2011; Accepted: 01-02-2012

| March 2012 Special Issue (1) | Journal of Research in Medical Sciences S1

 Omranifard, et al.: Sertraline addition for depressive symptoms in stable schizophrenia

schizophrenic  patients,  especially  during  maintenance  ment  of  depressive  symptoms  with  this  drug,  we 
therapy, are essential. Otherwise, the prognosis andthe  aimed to compare the efficacy of sertraline with place‐
quality of life achieved through treatment will be quite  bo  in  the  treatment  of  depressive  symptoms  in  schi‐
poor.  zophrenic  patients  who are  not  in  active  phase  with  a 
  specific  scale  named  Calgary  Depression  Scale  for 
A meta‐analysis has been performed on results of trials  Schizophrenia  (CDSS)  which  has been used seldom in 
that  have  investigated  the  clinical  efficacy  of  antide‐ previous studies  [9]. CDSS was the first scale specifical‐
pressant  medication  (either  tricyclics,  SSRIs  or  others)  ly designed and validated for the evaluation of depres‐
in  the  treatment  of  depression  in  schizophrenic  pa‐ sive  symptoms  in  patients  with  schizophrenia  [24];  and 
tients  [9]. In this study in a subset of five trials (209 pa‐ has  been  shown  not  to  overlap  with  negative  symp‐
tients),  the  proportion  improved  in  the  antidepressant  toms and extrapyramidal symptoms [24, 26]. 
group was higher than in the placebo group and there   
was no evidence that antidepressant treatment induced  METHODS
a  deterioration  of  psychotic  symptoms  in  these  trials.   
The use of newer antidepressants in combination with  Subjects:  
antipsychotics  to  treat  the  depressive  symptoms  of  With  confidence  of  95  %  and  power  of  80  %  and  also 
schizophrenia  is  encouraged  because  of  significantly  estimation  of  clinical  standard  deviation  of  schizoph‐
more  side  effects  in  other  antidepressants  such  as  renia  in  both  control  and  intervention  groups  which 
TCAs [10, 11] and by positive results compared to placebo  was  1.6  of  CDSS  changes  range,  study  subjects  were 
in the studies of augmentation of antipsychotics.  determined  as  30  patients  in  both  groups.  Patients 
  were chosen from both admitted or outpatients, in the 
Siris  studies  revealed  that  SSRIs  were  the  most  fre‐ psychiatric  ward  or  clinic  of  Isfahan  Noor  Hospital 
quently  prescribed  antidepressants,  and  the  preferred  respectively. All of them had a diagnosis of schizoph‐
combination  was  an  atypical  antipsychotic  plus  an  renia. All subjects met the following inclusion criteria: 
SSRI  [12].  There  are  several  published,  trials  examining  1)  16‐65  years  aged;  2)  receiving  a  stable  dose  of  an 
SSRIs  in  the  treatment  of  depressive  symptoms  in  pa‐ atypical  antipsychotic  medication;  3)  to  be  clinically 
tients  with  schizophrenia  and  have  provided  mixed  stable;  4)  diagnosed  with  post  psychotic  depressive 
results.  These  trails  include  several  double‐blind,  pla‐ disorder  of  schizophrenia  according  to  DSM‐IV‐TR 
cebo‐controlled trials. In the trail with fluvoxamine  [13],  research criteria or clinically meaningful subsyndrom‐
the  difference  in  mean  HDRS  scores  between  the  two  al  depressive  symptoms.  Stability  was  defined  as  a 
groups  at the end of the study  period was  not  signifi‐ period  of  at  least  one  month  when  the  patient  main‐
cant. With fluoxetine, two of three studies demonstrat‐ tained  a  score  of  at  least  four  or  less  on  all  positive 
ed no benefit over placebo with regard to the treatment  symptoms of the Positive and Negative Symptoms Scale 
of depressive symptoms in patients with schizophrenia  (PANSS);  This  definition  is  based  on  that  used  by 
[14, 15], but in third study, Compared with placebo, fluo‐ Schooler and colleagues  [27], who used the Brief Psychia‐
xetine  treatment  led  to  a  slight  improvement  in  de‐ tric  Rating  Scale  and  patients  who  were  stabilized  on 
pressive symptoms  [16]. In two studies with citalopram,  antipsychotic  medication.  The  translation  and  back‐
no scales to assess depression were used  [17,  18] but In a  translation method was used to make the Persian trans‐
recent study citalopram was more effective than place‐ lation  of  PANSS  valid.  PANSS  was  translated  by  two 
bo in relieving depression, negative symptoms, mental  psychiatrists  to  Persian  and  then  two  other  bilingual 
functioning,  and  quality  of  life  of  older  patient  with  psychiatrists  translated  the  same  text  to  first  language. 
schizophrenia  [19].  In  one  of  studies  with  sertraline  Translated texts were evaluated by the translation team 
treating patients with remitted schizophrenia and ma‐ for  final decision. Subjects also met none of the follow‐
jor  depression  showed  no  benefit  [20];  but  in  another,  ing  exclusion  criteria:  1)  any  serious  medical  condition 
Sertraline‐treated  patients  showed  a  significant  im‐ that  would  interfere  with  safe  study  participation;  2) 
provement  on  the  anxiety/depression  subscale  of  the  any  substance  abuse  or  dependency  except  nicotine;  3) 
Brief Psychiatric Rating Scale (BPRS) [21].  pregnancy  or  nursing  in  women;  4)  using  any  of  psy‐
  chotropic drugs except atypical antipsychotics. 
Sertraline is an antidepressant drug that has proved to   
be effective in the treatment of depression, with fewer  Design and Procedures: 
side‐effects  than  tricyclics  [22],  protecting  against  the  The  study  used  a  randomized,  double‐blind,  placebo‐
recurrence  and  relapse  of  depression,  and  carrying  a  controlled  clinical  trial  design  with  an  active  medica‐
very  low  risk  of  exacerbating  psychotic  symptoms  [23].  tion  condition  and  a  matching  placebo,  which  was 
Considering lack of studies and mixed results of treat‐ done on year 2010. The study followed the Declaration 
S2 Journal of Research in Medical Sciences | March 2012 Special Issue (1) |
 Omranifard, et al.: Sertraline addition for depressive symptoms in stable schizophrenia

of Helsinki on Biomedical Research Involving Human  into the study. Thirty of participants randomized to the 
Subjects  and  was  approved  by  the  Ethics  Committee  sertraline condition, compared to thirty of participants 
from  the  Isfahan  University  of  Medical  Sciences.  All  randomized to placebo. Three patients were eliminated 
participants provided written informed consent. At the  from  placebo  group;  one  didnʹt  answer  the  phone, 
screening  visit,  after  providing  demographic  data,  eli‐ oneʹs family refused to continue the treatment and one 
gible subjects were randomly assigned to sertraline or  because  of  poor  compliance.  And  three  patients  were 
placebo (1:1). Those assigned to sertraline started at 50  eliminated from sertraline group; one for taking a trip 
mg/day  and  the  dose  was  raised  to  100  mg/day  after  and two because of drug side effects which were seda‐
four weeks, and 200 mg/day after eight weeks if partial  tion  and  GI  disturbances  (Figure  1).  The  age  range  of 
response was not seen.   subjects was 20‐56 years with mean ± of 34.1 ± 8.5. The 
  demographic  and  clinical  features  of  the  sample  are 
Efficacy and Safety assessments:  reported in (Table 1). There were no statistically signif‐
The  subjects  were  assessed  at  the  screening  visit,  icant imbalances on demographics or symptom severi‐
weeks  eight  and  twelve  by  the  CDSS  and  Global  As‐ ty between treatment groups at baseline. The only sig‐
sessment of Functioning (GAF) Scale. In each visit sub‐ nificant difference was that subjects assigned to place‐
jects  were  assessed  for  followings:  1)  urine  pregnancy  bo  were  more  likely  to  have  more  prolonged  illness  
test  for  women,  2)  drug  side  effects.  The  translation  (P = .004) (Table 1). 
and  back‐translation  method  was  used  to  make  the   
Persian  translation  of  CDSS  valid.  CDSS  was  trans‐ The  difference  between  mean  scores  of  CDSS  at  base‐
lated by two psychiatrists to Persian and then two oth‐ line  and  after  eight  and  twelve  weeks  of  intervention 
er  bilingual  psychiatrists  translated  the  same  text  to  was significant in the sample as a whole (both placebo 
first  language.  Translated  texts  were  evaluated  by  the  and sertraline group) (P < 0.001) (Table 2); but subjects 
translation team for final decision.  assigned  to  active  medication  demonstrated  a  signifi‐
  cantly greater percentage decline compared to placebo 
Statistical methods:  (P = .003) (Figure 2, Table 2). Although the randomiza‐
The  data  were  analyzed  using  the  SPSS  statistical  tion  was  generally  effective,  an  analysis  of  covariance 
package  version  18.0.  Descriptive  statistics  were  used  was conducted for duration of illness. 
to  determine  demographic  characteristics  from  the   
sample.  The  difference  between  intervention  groups  The difference between mean scores of GAF at baseline 
and  follow‐up  time  (time  effect)  were  determined  us‐ and  after  eight  and  twelve  weeks  of  intervention  was 
ing  ANOVA  repeated  measure  test.  P‐value  less  than  not  significant in  the  sample as a whole  (both  placebo 
0.05 showed a significant.  and  sertraline  group)  (P  =  .093)  (Table  2);  and  there 
  were  no  significant  differences  between  the  treatment 
This  study  was  done  on  year  2010  and  registered  in  groups (P = .453) (Figure 3, Table 2). 
IRCT with identifier IRCT201110187839N1.   
  Rates  of  side  effects  were  significantly  different  be‐
Results tween groups with no side effect in placebo group and 
  20.7  %  in  sertraline  group  (P  <  0.001).  The  most  com‐
A  total  of  101  individuals  screened  and  60  met  all  in‐ mon side effects were GI disturbances (n = 3) and seda‐
clusion  and  no  exclusion  criteria  which  randomized  tion (n = 2). 
 

Screened
(N = 101)

Excluded based on inclu-

sion/exclusion criteria
(N = 41)

Randomized to Sertraline or
Placebo
(N = 60)
Figure 1: Study design flow chart
| March 2012 Special Issue (1) | Journal of Research in Medical Sciences S3
 Omranifard, et al.: Sertraline addition for depressive symptoms in stable schizophrenia

 
Table 1: Demographics and clinical characteristics of subjects (n = 54)

Characteristics Sertraline Placebo P-value

N = 27 N = 27
Sex
Male 13 (48.1) 14 (51.9) .785
Female 14 (51.9) 13 (48.1)
Age, mean (±S.D.) 33.44 (6.95) 34.70 (10.2) .593
Marital status
Single 14 (51.9) 10 (37.0)
Married 7 (25.9) 13 (48.1) .413
Widow 3 (11.1) 2 (7.4)
Divorced 3 (11.1) 2 (7.4)
Education
Illiterate 5 (18.5) 4 (14.8)
Primary school 12 (44.4) 12 (44.4) .839
High school 8 (29.6) 7 (25.9)
College 2 (7.4) 4 (14.8)
Habitation
Alone 2 (7.4) 3 (11.1) .593
With parents 15 (55.6) 10 (37)
With family 10 (37) 14 (51.8)
Occupation
Employee 1 (3.7) 3 (11.1) .412
Self employed 14 (51.9) 15 (55.6)
Unemployed 12 (44.4) 9 (33.3)
Family number
≤2 25 (92.6) 23 (85.4) .604
≥3 2 (7.4) 4 (14.8)
Duration of disease
< 1 year 18 (66.7) 6 (22.2)
1-5 years 5 (18.5) 9 (33.3) .004
> 5years 4 (14.8) 12 (44.4)
No. of admission
No 5 (18.5) 8 (29.6)
1 time 9 (33.3) 8 (29.6) .649
≥ 2 times 13 (48.2) 11 (40.8)
Antipsychotic
Clozapine 7 (25.9) 9 (33.3) .551
Risperidone 10 (37.0) 8 (29.6) .564
Aripiprazole 2 (7.4) 4 (14.8) .669
Olanzapine 5 (18.5) 4 (14.8) .851
Quetiapine 3 (11.1) 2 (7.4) .865
CDSS, mean (±S.D.)
Before intervention 12.2 (3.4) 11.2 (2.4) .216
GAF, mean (±S.D.)
Before intervention 5.6 (1.7) 6.2 (1.6) .164
All variables are number (%) unless otherwise indicated.
CDSS = Calgary Depression Scale for Schizophrenia. GAF = Global Assessment of Functioning.
 
Table 2: Summarizes of Calgary Depression Scale for Schizophrenia (CDSS) and Global Assessment of Functioning
(GAF) scores in the patients based on eight and twelve weeks follow-up controlling for duration of illness using ANO-
VA Repeated measure

Main Effects F-test d.f. P-value

CDSS:
Follow-up (time effect) 12.4 (2,48) <.001
Intervention (group effect) 9.9 (1,49) .003
Follow-up *Intervention (interaction effect) 22.9 (2.48) <.001
GAF:
Follow-up (time effect) 2.5 (2,51) .093
Intervention (group effect) .571 (1,52) .453
Follow-up *Intervention (interaction effect) 2.7 (2.51) .072

S4 Journal of Research in Medical Sciences | March 2012 Special Issue (1) |

 Omranifard, et al.: Sertraline addition for depressive symptoms in stable schizophrenia

Figure 2: Change in the Calgary Depression Scale for Schizophrenia (CDSS)

Figure 3: Change in the Global Assessment of Functioning (GAF)

 
Table 3: Frequency and Mean (SD) score of Calgary Depression Scale for Schizophrenia (CDSS) and Global Assess-
ment of Functioning (GAF) in weeks zero, eight and twelve
SCALE Intervention Control P-value
Mean (SD) Mean (SD)
CDSS
Before intervention 12.2 (3.4) 11.2 (2.4) .216
After 8weeks 10.6 (2.7) 11.6 (2.5) .163
After 12weeks 9.2 (2.7) 11.8 (2.6) .001
GAF
Before intervention 5.6 (1.7) 6.2 (1.6) .164
After 8weeks 6 (1.5) 6.3 (1.5) .520
After 12weeks 6.1 (1.4) 6.1 (1.4) 1
 
| March 2012 Special Issue (1) | Journal of Research in Medical Sciences S5
 Omranifard, et al.: Sertraline addition for depressive symptoms in stable schizophrenia

DISCUSSION ly effective but subjects assigned to placebo were more 
  likely  to  have  more  prolonged  illness  (P  =  .004),  so  an 
Studies of depressive symptoms in schizophrenia have  analysis  of  covariance  was  conducted  for  duration  of 
used  a  variety  of  measures,  and  non  specific  scales  illness. 
(such  as  Hamilton  Depression  Rating  Scale  or  Beck       
Depression Inventory) are the most commonly used in  Also  the  difference  between  mean  scores  of  GAF  was 
spite  of  the  fact that  these  scales  do not allow  the  dis‐ not  significant  in  two  arms of study but  after  8 weeks 
tinction of depressive from negative symptoms in schi‐ the  improvement  was  better  in  sertraline  group  and 
zophrenic  patients  (Micallef  et  al.,  2006)  [9];  studies  on  this  was  clinically  obvious.  This  improvement  in  pa‐
fluvoxamine  (Silver  et  al.,  1992)  [13],  fluoxetine  (Bucha‐ tients with chronic schizophrenia is a matter of concern 
nan  et  al.,  1996;  Goff  et  al.,  1995)  [14,  15]  and  sertraline  and  is  consistent  with  improvement  in  depressive 
(Mulholland et al., 2003)  [21] which used these non spe‐ symptoms.  A  double‐blind  study  with  citalopram 
cific  scales  had  mixed  results.  We  used  Calgary  De‐ (Kasckow  et  al.,  2010)  [28]  also  showed  higher  mental 
pression Scale for Schizophrenia (CDSS) which was the  functioning  and  quality  of  life  scale  (QOLS)  scores 
first  scale  specifically  designed  and  validated  for  the  compared  to  the  placebo  group.  These  results  suggest 
evaluation  of  depressive  symptoms  in  patients  with  that improvement in depressive symptoms in  patients 
schizophrenia (Addington et al., 1993) [24]; this scale has  with  stable  schizophrenia  may  cause  improvement  in 
been  shown  not  to  overlap  with  negative  symptoms  their general function and quality of life which is very 
and extrapyramidal symptoms (Addington et al., 1994;  important in prognosis of chronic cases.  
Collins  et  al.,  1996)  [25,  26].  Results  of  this  twelve  week,   
double‐blind  study  suggest  that  sertraline  is  more  ef‐ Also the rate of side effects was little but it was signifi‐
fective  than  placebo  in  improving  depressive  symp‐ cantly  more  in  sertraline  group  and  in  two  subjects 
toms.  Also  the  difference  between  mean  scores  of  resulted  in  missing  the  patient.  This  is  noteworthy, 
CDSS  at  baseline  and  after  eight  and  twelve  weeks  of  because  poor  compliance  is a matter  of concern  in  pa‐
intervention was significant in both placebo and sertra‐ tients with chronic diseases like schizophrenia. 
line  groups  but  repeated  measures  of  ANOVA  re‐  
vealed  a  significant  main  effect  for  group,  time,  and  ACKNOWLEDGMENTS
interaction of group and time which revealed that sub‐ We  would  like  to  express  thanks  for  Behavioral 
jects  assigned  to  active  medication  had  a  significantly  Sciences Research Center of Isfahan University of Med‐
greater percentage decline compared to placebo. This is  ical Sciences. This study is posted on www.irct.ir with 
not  consistent  with  a  double‐blind  study  with  sertra‐ identifier  IRCT201110187839N1.  This  paper  is  derived 
line which also used CDSS as a rating scale (Addington  from a specialty thesis in Isfahan University of Medical 
et al., 2002) [20]; it could be due to lack of dose and dura‐ Sciences. 
tion of treatment in that study (maximum 100 mg and   
six weeks respectively) (Addington et al., 2002)  [20]. We  REFERENCES
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How to cite this article: Omranifard V, Mohammad Hosseini Gh,
Sharbafchi MR, Maracy M, Ghasemi Fm Aminoroaia M. Sertraline as an
add-on treatment for depressive symptoms in stable schizophrenia: a
double-blind randomized controlled trial. J Res Med Sci 2012; 17(4) Special
Issue 1: S1-S7.
Source of Support: This study is funded by Behavioral Sciences Research
Center of Isfahan University of Medical Sciences, Conflict of Interest: The
authors have no conflicts of interest.
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