Working PaperPDF Available

Schizophrenia-negative symptoms: a real, lasting challenge. Retrospective and cross-sectional study

Authors:
Schizophrenia-negative symptoms: a real, lasting challenge.
Retrospective and cross-sectional study
Mamdouh M. Al Gamal, Maha M. Al Tayebani and Rasha E. Bassim
Department of Neuropsychiatry, Institute of Psychiatry,
Faculty of Medicine, Ain Shams University, Dubai, UAE
Correspondence to Rasha E. Bassim, MD, Department
of Neuropsychiatry, Institute of Psychiatry, Faculty of
Medicine, Ain Shams University, United Arab Emirates,
Dubai City, Mirdif, st. 15, Compound 9 B, Dubai
Tel: + 97142850450;
e-mail: rashabassim2@gmail.com
Received 9 June 2012
Accepted 20 October 2013
Middle East Current Psychiatry
2014, 21:11–21
Background
Negative symptoms of schizophrenia, account vastly for its functional disability and
often persist despite pharmacological treatment.
Aim
The aim of the study was to detect cases of resistant negative schizophrenia in
institutionalized patients, compare between groups of resistant and nonresistant
cases, formulate comprehensive criteria for resistant schizophrenia with different
positive and negative symptoms, and find predictors of resistance.
Patients and methods
According to DSMIV-SCID, 95 chronic schizophrenia patients were examined by
BPRS, PANSS, CGIS, and MMSE. Clinical data, treatment history, and medical state
were collected. Operational definition for negative resistant schizophrenia was
acquired from PANSS and CGIS scores, and Modified Kane’s criteria for resistant
schizophrenia. Cases were divided into four groups: resistant schizophrenia with
predominant negative symptoms (n= 26), resistant schizophrenia (modified Kane’s
criteria) (n= 25), overlapped resistant cases (n= 11), and nonresistant cases (n= 33).
Results
Resistant schizophrenia patients and cases with predominant negative symptoms scored
significantly higher (P=37.19±7.3)onmeannegativescores(P= 0.000), as well as all
resistant groups (n= 62) compared to nonresistant cases (n= 33) (P= 0.000, mean 34.0 8 ±
8.9). Resistant negative schizophrenia group scored significantly lower on MMSE (P= 0.05).
The most powerful predictors for resistant negative schizophrenia were cognitive deficits
presented by low score in MMSE, high score on disorientation and lack of attention items.
Conclusion
Presence of subgroup of patients with predominant negative symptoms, and not
included in the definition of resistant schizophrenia, indicates that the available
diagnostic criteria need to be reviewed. Cognitive dysfunction linked to negative
schizophrenia suggests a bidirectional effect and possibility of a biological
predisposition behind resistance other than social or environmental factors.
Keywords:
cognitive dysfunction in schizophrenia, negative schizophrenia, resistant schizophrenia
Middle East Curr Psychiatry 21:11–21
&2014 Institute of Psychiatry, Ain Shams University
2090-5408
Introduction
Negative symptoms have received considerable attention
over the past several decades as they have been found to
be associated with poor functional outcome, poor
treatment response, and biological correlates that differ
from other symptoms of schizophrenia [1].
A factor complicating research in this area is that negative
symptoms can be caused by a number of factors that result
in varied manifestations of illness. Although efforts thus far
to elucidate a distinct schizophrenia subtype on the basis
of negative symptoms have yielded mixed results [2], yet,
in an attempt to address this issue, Carpenter et al.[3]
proposed that negative symptoms could be viewed in
relation to whether they are persistent versus transient as
well as whether they are primary idiopathic to the illness or
secondary to factors other than the disease process (e.g.
medication effects, depression, and anxiety). Patients who
show multiple negative symptoms that are considered to be
both primary and enduring (41 year) fulfill criteria for the
deficit syndrome – a putative subtype within the broader
diagnosis of schizophrenia. Support for this classification
comes from numerous studies showing that the deficit and
nondeficit forms of schizophrenia differ on several key
domains, such as biological correlates, risk factors, and
etiology. The deficit syndrome has also been found to be
particularly resistant to current pharmacological and psy-
chosocial treatments, which may at least in part be because
of a symptom presentation and course of illness that differs
from patients with nondeficit schizophrenia [4–6].
The deficit syndrome represents a persistently impaired
subsample of schizophrenic patients, with continuous
social, occupational, and symptom impairment. In contrast,
Original article 11
2090-5408 &2014 Institute of Psychiatry, Ain Shams University DOI: 10.1097/01.XME.0000438136.13691.48
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
patients with nondeficit syndrome schizophrenia showed at
least some periods of remission or recovery, with the
likelihood of these periods increasing as they became older.
Findings provide further support for the validity of the
deficit syndrome concept and suggest that deficit status is
characterized by a more persistently impaired course of
illness and particularly poor long-term prognosis [7]. One
potential interpretation of the above evidence is that the
deficit group simply has a more severe form of the same
illness as nondeficit schizophrenia [8].
As the negative symptoms of schizophrenia have been
considered to be a psychiatric form of the frontal lobe
syndrome [9], schizophrenia researchers have established
relationships between individual negative symptoms and
abnormal frontal lobe circuitry, among of which are the
abnormalities in neural circuits governing both eye track-
ing [10], which appears to be impaired in patients with
deficit-negative symptoms, and olfactory deficits, which
appear to be associated with avolitional symptoms [11].
Although the introduction of second-generation antipsy-
chotics (SGAs) during the 1990s was accompanied by
reports suggesting that these agents comprised a break-
through in the treatment of negative symptoms [12], in
current practice, recovery of patients with negative
symptoms has remained elusive. Currently available treat-
ments for negative symptoms appear to have modest
benefits, with the result that negative symptoms continue
to limit patient recovery disproportionately. Treatment
guidelines recommend that in order to optimize functional
outcomes for patients with schizophrenia, psychosocial
programs or psychiatric rehabilitation should be combined
with pharmacological management [13]. Yet, for patients
with negative symptoms, participation in these programs
may not only be more difficult but also less efficacious.
According to one study, patients with the more severe
‘deficit’ form of schizophrenia who were enrolled in social
skills training experienced less benefit than nondeficit
patients. The available pharmacological treatments used
to reduce the burden of negative symptoms have limited
benefits, which is evident from accumulated recent
intervention studies consistently showing either small
effect sizes or inconsistent results. In particular, the
expectation that negative symptoms would show differ-
entially improved responsiveness to SGAs compared with
first-generation neuroleptics has not been rea1ized to a
degree that is clinically significant [5].
For clinicians, meaningful interpretation of any forth-
coming data on new adjunctive treatment will depend on
a clarification of the nosology of negative symptoms. The
current understanding, that negative symptoms are
restricted to schizophrenia and form a single domain,
appears to be less certain than previously. A definite
conceptualization would need to address whether nega-
tive symptoms should be considered homogeneous or
heterogeneous, categorical, or dimensional, and whether
and how they are distributed beyond patients with
schizophrenia, as suggested by some studies [14,15].
It is found that negative symptom severity was positively
and significantly correlated with later occupational
impairment, financial dependence on others, impaired
relationships with friends, impaired ability to enjoy
recreational activities, and global assessment of function-
ing. The magnitudes of correlation between the levels of
psychotic symptoms or disorganized symptoms and 2-year
quality-of-life measures were comparatively lower [16].
Aim
Because of the importance of negative symptoms of
schizophrenia for outcome, response to treatment, social
and functional abilities, and skills of these patients, and
being a real challenge, this study aimed to detect cases of
resistant negative schizophrenia in institutionalized
patients with schizophrenia, make a comparison between
different groups of resistant and nonresistant cases,
formulate comprehensive criteria for resistant schizo-
phrenia with different positive and negative symptoms,
and find predictors of resistant negative schizophrenia.
Patients and methods
Duration and place of the study
The current study was carried out during the last 6 months
of the year 2010 at the Psychological Medicine Hospital,
Kuwait, which is the only governmental psychiatric hospital
intheentireestateofKuwait,with764beds,358ofwhich
are in the general psychiatry admission wards; 131, 50, 36,
and 189 beds serve the rehabilitation, geriatrics, forensic
psychiatry, and addiction treatment wards, respectively. A
total of 95 patients with chronic schizophrenia treated in
long-stay hospital wards were interviewed by each author
separately, for greater reliability.
Tools
Structured clinical interview for DSM-IV Axis I Diagnosis
Clinical version 9 (Arabic version) [17]
It is used for verification of diagnosis and it is a
semistructured diagnostic interview based on an efficient
but thorough clinical evaluation administered by an
experienced trained bilingual researcher for Arabic-speaking
patients. Accordingly, a retrospective file review was carried
out to collect baseline data such as sociodemographics,
clinical and anthropometric characteristics, medical condi-
tions, treatment traits, state of response, causes of drug
changes, and current medication.
Then, each of them was assessed using the following:
The Positive and Negative Syndrome Scale (PANSS) [18]
It is used for rating patients’ symptoms and it includes
30 items on three subscales: seven items covering
positive symptoms, seven items covering negative symp-
toms, and 16 items covering general psychopathology.
Each item is scored on a seven-point item-specific scale
ranging from 1 to 7; thus, the positive and negative
subscales each range from 7 to 49 and the general
psychopathology scale ranges from 16 to 112. It is a
standard tool for assessment of clinical outcome in
12 Middle East Current Psychiatry
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
treatment studies of psychotic disorders and is useful for
tracking severity in clinical practice.
The Brief Psychiatric Rating Scale (BPRS) [19]
It is a short scale for measuring the severity of psychiatric
symptomatology. Its 18 items are rated on a seven-point
item-specific scale from 0 to 6, with the total score
ranging from 0 to 108.
The Clinical Global Impression (CGI-S) [20]
It is a seven-point scale that requires the clinician to
rate the severity of the patient’s illness at the time
of assessment, relative to the clinician’s past ex-
perience with patients who have the same diagnosis.
Considering the total clinical experience, a patient is
assessed on severity of mental illness at the time of rating.
The Mini-Mental State Examination (MMSE) [21]
It is a 30-point cognitive test developed for bedside
assessment of cognitive functions including orientation,
memory, attention, construction, and language.
For diagnosis of resistant schizophrenia
The Kane et al. [22] criteria were modified; we used the
criterion failure of three instead of two different
antipsychotic trails for (3–6 months) instead of 6 weeks,
on the basis of valid available information, such as:
(1) Clinical profile of our patients who are chronically
hospitalized and have been using antipsychotic
medications for 3 months or more.
(2) Most of the clinical trials (CATI and CUTLASS)
assess patients at after at least 6–8 weeks to
determine responsiveness and after at least 12 weeks
to determine efficiency, where resistance assessment
requires a much longer duration. Thus, the authors
considered a 3-month duration (more than 12 weeks)
to be valid enough in order to determine resistance to
treatment.
For the diagnosis of negative resistant schizophrenia
The authors established some operational criteria on the
basis of clinical profile, the above-mentioned durations,
and a lower negative PANSS subscale as follows:
(1) Total negative PANSS score of at least 25.
(2) Total positive PANSS score less than 20.
(3) Two or more of negative symptoms scored of at least
4 on the negative PANSS subscale.
(4) CGI-S score of at least 4 with moderately to
extremely ill range.
(5) Failure of two different antipsychotic trails (3–6
months).
(6) Impaired functional abilities in the last 2 years.
Accordingly, patients were divided into four groups:
(1) Resistant schizophrenia according to modified Kane’s
criteria (1988).
(2) Negative resistant schizophrenia on the basis of our
operational criteria.
(3) Overlapped cases of the previous two groups.
(4) Nonresistant cases.
New defining criteria were established for all resistant
schizophrenia groups using different cutoff scores for
PANSS and CGI-S, depending on their specificity,
sensitivity, and predictive values, and diagnostic accuracy
was also applied.
Ethical issue
The study was approved by the local ethical research
committee of the hospital after obtaining oral and/or
written consent from the patients and their families.
Statistical analysis
Data were collected, coded, and then entered into an IBM
compatible computer; using the SPSS, version 17 (SPSS
Inc., Chicago, Illinois), data entered were checked for
accuracy and then for normality using the Kolmogorov–
Smirnov test. Qualitative variables were expressed as
number and percentage whereas quantitative variables
were expressed as mean (X) and SD. The arithmetic
mean (X) was used as measures of central tendency,
whereas SD was used as a measure of dispersion.
The following statistical tests were used:
Independent-samples t-test was used as a parametric test
of significance for comparison between two sample means
after performing Levene’s test for equality of variances.
Table 1 Comparison between different resistant and
nonresistant schizophrenic groups according to PANSS scores
NM SD P-value
Total positive PANSS subscore
Pure no resistance 33 16.42 6.062
Kane’s resistant 25 25.92 4.261
Negative resistant 26 11.85 3.663 0.000***
Overlap resistant 11 18.18 1.888
Total 95 17.87 7.008
Total negative PANSS subscore
Pure no resistance 33 18.00 5.006
Kane’s resistant 25 29.08 9.380
Negative resistant 26 37.19 7.327 0.000***
Overlap resistant 11 38.09 6.172
Total 95 28.49 10.945
Total general psychopathology of the PANSS subscore
Pure no resistance 33 31.88 8.859
Kane’s resistant 25 44.28 6.955
Negative resistant 26 36.46 5.413 0.000***
Overlap resistant 11 47.00 9.413
Total 95 38.15 9.489
Total positive PANSS subscore
Nonresistance 33 16.42 6.062
All resistance group 62 18.65 7.393 0.142
Total 95 17.87 7.008
Total negative PANSS subscore
Nonresistance 33 18 5.006
All resistance group 62 34.08 8.952 0.000***
Total 95 28.49 10.945
Total general psychopathology of the PANSS subscore
Nonresistance 33 31.88 8.859
All resistance group 62 41.48 8.063 0.000***
Total 95 38.15 9.489
PANNS, Positive and Negative Syndrome Scale.
Significant if Po0.05.
***Highly significant if Po0.001.
Schizophrenia-negative symptoms Al Gamal et al. 13
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
The w
2
-test (or likelihood ratio) was used as a nonpara-
metric test of significance for comparison between the
distribution of two qualitative variables.
Fisher’s exact test was used as a nonparametric test of
significance for comparison between the distributions
of two qualitative variables whenever the w
2
-test was
not appropriate; it yielded the P-value directly.
The paired-sample t-test was used as a parametric test of
significance for comparison of before and after values
of quantitative variables.
The one-way analysis of variance (F-test)wasusedasa
parametric test of significance for comparison between more
than two sample means using either Scheff’s or Tamhane’s
post-hoc tests for results of homogeneity testing.
The Pearson correlation coefficient (r) was used as a
parametric measure of the mutual relationship between
two normally distributed quantitative variables.
Validating parameters were calculated, namely, sensitivity,
specificity, positive predictive value (PPV), negative
predictive value (NPV), and diagnostic accuracy for the
individual criteria of metabolic syndrome in chronic
patients with schizophrenia.
Sensitivity, the ability of the test to detect those with the
condition.
Specificity, the ability of the test to exclude those
without the condition.
PPV, the ability of the test to detect those with the
condition among positive screeners.
NPV, the ability of the test to exclude those without the
condition among negative screeners.
Diagnostic accuracy, the percentage of total agreement of
both methods for true positive and true negative values.
Multivariable logistic regression analysis for the predic-
tion of metabolic syndrome and diabetes mellitus (DM).
A 5% level was chosen as the level of significance in all
statistical significance tests used.
Results
Define resistant negative schizophrenia
On studying the 95 patients with chronic schizophrenia,
36 patients were found to be resistant on the basis of
Kane’s criteria. It is noted that most of the cases with high
total negative scores and CGI-S scores were not included.
Table 2 Comparison between nonresistant and resistant schizophrenia groups according to clinical characteristics, medical state,
and anthropometric characteristics
Symptoms Nonresistant Kane’s resistant Negative resistant Overlap resistant Total P-value
Type of Symptoms at onset
Negative 0 0 3 0 3
Positive 27 22 17 6 72
Mixed 6 3 6 5 20 0.04*
Total 33 25 26 11 95
Schizophrenia subtype
Residual 4 1 7 2 14
Undifferentiated 13 8 14 6 41
Paranoid 9 9 2 2 22 0.009***
Disorganized 0 6 3 1 10
Schizoaffective 7 1 0 0 8
Total 33 25 26 11 95
Family history of psychiatric illness
Negative 14 12 16 5 47
Positive 19 13 10 6 48 0.52
Total 33 25 26 11 95
Family history of medical illness (diabetes mellitus, hypertension, dyslipidemia)
Negative 17 16 25 7 65
Positive 16 9 1 4 30 0.003***
Total 33 25 26 11 95
Diabetes
Negative 20 16 21 10 67 0.13
Positive 13 9 5 1 28
Total 33 25 26 11 95
Hypertension
Negative 18 19 20 9 66
Positive 15 6 6 2 29 0.14
Total 33 25 26 11 95
Dyslipidemia
Negative 13 14 15 7 49
Positive 20 11 11 4 46 0.36
Total 33 25 26 11 95
BMI
430 19 11 12 7 49
25–29.9 10 11 7 1 29 0.28
o25 4 3 7 3 17
Total 33 25 26 11 95
*Significant if Po0.05.
***Highly significant if Po0.001.
14 Middle East Current Psychiatry
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
The operational definition for negative resistant schizo-
phrenia was applied with a cutoff point for total negative
PANSS of at least 25 and a total positive score of PANSS
less than 20 with CGI-S score of at least 4.
According to our operational definition, a total of 37
patients had negative resistant schizophrenia and 36
patients had resistant schizophrenia on the basis of
Kane’s criteria. Then, the cross-tabulation between cases
yielded four groups of schizophrenia as follows: negative
resistant schizophrenia (n= 26) (27.4%), Kane’s resistant
schizophrenia (n= 25) (26.3%), overlapped resistant
cases (n= 11) (11.6%), and nonresistant schizophrenia
(n= 33) (34.7%), with a total of 62 (65.3%) patients with
resistant schizophrenia.
Differences between resistant groups and nonresistant
cases
As shown in Table 1, Kane’s resistant group score was
significantly higher on the positive PANSS subscale
(P= 0.000, mean = 25.9 ± 4.2) and the general psycho-
pathology subscale (P= 0.000, mean = 44.2 ± 6.9) than
the other groups, whereas negative resistant cases scored
significantly higher on the negative PANSS subscale
(P= 0.000, mean = 37.19 ± 7.3) compared with the
others. Moreover, the difference between all resistant
groups (n= 62) versus nonresistant cases was significant
(P= 0.000) on negative PANSS scores and general
psychopathology scores, but not on the positive subscale
(P= 0.14).
The negative resistant group and overlapped cases –
which originally scored higher on negative scores of
PANSS (38.09 ± 6.1) compared with positive scores
(18.1 ± 1.8) – showed a significant correlation
(P= 0.05) with lower scores of MMSE (16.15 ± 6.8 and
15.9 ± 8.9, respectively) as can be seen in Table 1.
However, the absence of a family history of medical
illness (DM, hypertension, dyslipidemia) correlated
significantly with negative schizophrenia (P= 0.003).
Also, the negative resistant group was significantly more
distributed among residual and undifferentiated schizo-
phrenia subtypes (P= 0.009) (n= 7 and 14), respectively,
as can be seen in Table 2.
Table 3 shows that there was no other significant difference
between all resistant groups and nonresistant cases in other
sociodemographics, clinical characteristics, medical state,
anthropometric characteristics, and treatment history.
However, in terms of the CGI-S scale scores, a significant
difference was observed between resistant and nonresis-
tant patients (P= 0.000), where all resistant cases were
distributed as markedly, severely, or extremely ill (score
>4), whereas nonresistant cases were distributed on the
moderate and borderline scale (score r4), as shown
in Table 4.
Table 3 Comparison between nonresistant and different resistant schizophrenia groups according to sociodemographics and
clinical characteristics
Nonresistant Kane’s resistant Negative resistant Overlap resistant Total P-value
Sex
Female 8 1 3 3 15
Male 25 24 23 8 80 0.92
Total 33 25 26 11 95
Marital status
Single 21 20 17 10 10
Married 6 2 3 1 12
Divorced 5 3 5 0 13
Widow 1 0 1 0 2 0.52
Total 33 25 26 11 37
Job
Jobless 23 19 17 10 69
Professional 0 0 1 0 1
Retired 10 6 8 1 25 0.49
Total 33 25 26 11 95
Education
Illiterate 5 4 10 3 22
Low grade 21 14 11 7 53
High grade 6 6 5 0 17 0.31
University 1 1 0 1 3
Total 33 25 26 11 95
Social standard
Very low 11 5 9 1 26
Low 19 18 15 8 60
Moderate 3 2 2 1 8 0.50
High moderate 0 0 0 1 1
Total 33 25 26 11 95
Clinical global comparison severity index
Borderline ill 12 1 0 0 13
Moderate ill 14 3 1 0 18
Marked ill 7 6 10 4 27 0.000
Severely ill 0 9 8 4 21
Extremely ill 0 6 7 3 16
Total 33 25 26 11 95
Significant if Po0.05.
Highly significant if Po0.001.
Schizophrenia-negative symptoms Al Gamal et al. 15
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
Differences in the positive and negative PANSS scores
Table 4 shows that patients who did not develop diabetes
or metabolic syndrome scored significantly higher on the
negative subscale of PANSS (P= 0.03, mean = 30.3 ± 10.6
for DM) and (P= 0.007, mean = 34.6 ± 9.1 for metabolic
syndrome).
Meanwhile, negative PANSS scores were significantly
higher in marked, severely, and extremely ill scores (44)
of CGI-S (P= 0.000) (26.9 ± 8.1, 36.1 ± 8.7, and 39.8 ±
8.2), respectively. This means that cases with higher
negative PANSS scores had more cognitive dysfunction and
impaired global functioning, as shown in Table 4.
Although the total negative PANSS scores showed an
inverse significant correlation with BMI (P= 0.002), the
total negative PANSS scores correlated highly signifi-
cantly with lower MMSE scores and disorientation, and
lack of attention scores of the general psychopathology
subscale of PANSS (P= 0.001, 0.000, 0.000) respectively,
as can be seen in Table 5.
Tables 5 and 6 show that there was no other significant
association for total negative scores, and total positive
PANSS scores showed no significant associations or
correlations in terms of sociodemographic, clinical med-
ical, and anthropometric characteristics and treatment
history.
Predictive value and diagnostic accuracy for resistant
schizophrenia
The logistic regression model (w
2
= 14.051), significant
at 0.04 and R
2
= 0.186, showed that the powerful predictive
variable for negative resistant schizophrenia cases was
cognitive dysfunction including lower MMSE if less than
20 [0.195, odds ratio (OR) = 1.2)] (0.422–3.504) and a
higher disorientation score (0.450, OR = 1.046) (0.709–2.54)
and higher lack of attention scores (0.406, OR = 1.50)
(0.941–3.391), as can be seen in Table 7.
Table 8 shows that other variables such as age, onset of
schizophrenia, number of repeated hospitalizations,
duration of illness, and sociodemographic status showed
no significant predictive power.
New definition for resistant schizophrenia
In attempts to create new cutoff points and definitions of
resistant schizophrenia in chronic cases that include
positive and negative symptoms, different cutoff points
for positive and negative total PANSS scores on the basis
of mean scores or lower mean scores as well as clinical
assessment, cutoff positive scores (Z16, Z20, Z23, and
Z25), cutoff points negative scores (Z20, Z23,
and Z25), cutoff points for general psychopathology
score of at least 39, and at least 4 cutoff points for CGI-S
scores were examined, and the results indicate that with
higher cutoff points of positive PANSS scores (Z16 to
Z25), sensitivity decreased (62.9–30.6) and diagnostic
accuracy also decreased (55.7–53.5), with a stable NPV
(around 35). However, specificity increased (42.4–82.3)
and the PPV increased (67.2–84.2). With higher cutoff
points of negative PANSS scores (Z20–7.25), sensitivity
decreased (91.9–88.7), whereas specificity increased
(51.5–94.12), the PPV increased (78.08–96.49), the NPV
increased (77.2–82.05), and diagnostic accuracy increased
(77.8–90.63), as shown in Table 9.
Finally, we may propose that from statistical and clinical
points of view, the criteria for resistant schizophrenia that
include positive and negative symptoms are as follows:
(1) Total positive score cutoff points Z16, total negative
score cutoff points Z23, total psychopathology cutoff
points Z39, clinical global impression score Z4, at
least two items of positive or negative symptoms on
PANSS score Z4, MMSE Score r20.
(2) Two failed previous trials of different antipsychotic
categories with full therapeutic dosage (Z1000 mg
chlorpromazine equivalent) for at least 3 months
(12 weeks’ duration).
(3) Poor functioning in the last 2 years.
Discussion
Challenges of negative schizophrenia
Negative symptoms are fundamental to schizophrenia
because of their predominance in the prodromal phase
and their tendency to be fairly stable over the course of
illness [23]. Controversy surrounds whether SGAs are
Table 4 Comparison of total positive and negative PANSS
subscores according to medical state, family history, and
clinical characteristics
Total negative scores Total positive scores
P N M/SD P N M/SD
Housing
No Private 26 25.6 ± 7.00 26 16.3 ± 6.3
Private 0.11 69 29.5 ± 11.20 0.20 69 18.4 ± 7.1
Diabetes
Negative 67 30.3 ± 10.60 67 17.6± 7.01
Positive 0.034 28 24.8 ± 10.90 0.55 28 18.5 ± 6.8
Hypertension
Negative 66 19.1 ± 10.10 66 18.4 ± 7.008
Positive 0.35 29 26.9 ± 12.70 0.26 29 16.8 ± 6.9
Dyslipidemia
Negative 49 30.3 ± 10.10 49 17.7± 7.1
Positive 0.92 46 26.5 ± 11.50 0.84 46 18.02 ± 6.9
Metabolic syndrome
Normal 9 34.6 ± 9.10 9 18.6 ± 7.9
Risky 17 33.5 ± 10.50 17 18.9 ± 9.4
High risky 0.007*** 47 27.9 ± 10.50 0.83 47 17.1± 6.9
Definite 22 23.1 ± 11.40 22 18.4 ± 6.7
Treatment category
Conventional 23 25.6 ± 12.30 23 16.5 ± 7.9
Atypical 0.15 72 29.4 ± 10.30 0.30 72 18.2 ± 6.6
Current atypical drug
Clozapine 37 28.6 ± 10.50 37 20.2 ± 6.5
Olanzapine 9 25.2 ± 10.70 9 17.6± 6.1
Respiridone 0.26 19 30.7 ± 10.07 0.15 19 16.1 ± 6.7
Quetiapine 7 34.7 ± 8.70 7 17.5 ± 6.2
Aripiperazole 1 33.0 ± 0.00 1 7.00 ± 0.00
CGI-S
Borderline ill 13 15.0 ± 2.40 13 16.0 ± 3.4
Moderate ill 18 21.3 ± 3.80 18 18.5 ± 5.6
Marked ill 27 26.9 ± 8.10 27 18.8 ± 6.4
Severely ill 0.000*** 21 36.1 ± 8.70 0.81 21 20.1 ± 8.03
Extremely ill 16 39.8 ± 8.20 16 17.5 ± 7.5
PANNS, Positive and Negative Syndrome Scale.
Significant if Po0.05
***Highly significant if Po0.001.
16 Middle East Current Psychiatry
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
more effective than finest generations in the treatment of
negative symptoms [24,25]. However, Buckley and
Stahl [26] concluded that treatment results of negative
symptoms to date have generally been disappointing. In
CATI study phase II, the overall conclusion was that
clozapine-treated patients fared better, for despite that
other group of patients treated with Olanzapine, Risper-
idone and Quetiapine scored higher values than the
Clozapine group, yet the benefit on negative symptoms
was modest and not statistically significant [27]. In
addition, it has been suggested that if clozapine, and
perhaps other SGA, lead to some improvement in
negative symptoms, they act as a facilitator effect in
enhancing the patients’ capacity to engage in psychoso-
cial therapies and these therapies may be the real contributor
toward improvements in negative symptoms [28].
In the current results using the operational definition for
schizophrenia resistance with predominantly negative
symptoms (total negative score Z25, total positive score
< 20 for PANSS and CGI-S Z4, with two or more
negative symptoms score Z4), it was found that 26
patients, with resistance to several drug traits including
clozapine and SGAs, did not fulfill the modified Kane
criterion (Goldstander) for the definition, which raises
the question of definition criteria for schizophrenia
resistance and also indicates an unnoticed subgroup
of patients with greater challenge and functional
disability [4,29].
One of the most striking results in our sample is that
cognitive dysfunction was the only factor with predictive
power for negative schizophrenia in logistic regression
analysis other than the sociodemographics and clinical
characteristics. The link between cognitive dysfunction
and negative schizophrenia is undisputed [30].
Neurocognitive impairment may lock patients into cycles
of repeated setbacks and failures, including inappropriate
goal setting and reduced ability to learn from errors [31].
These setbacks are theorized to foster dysfunctional
benefits including low expectancies for pleasure and
success, perception of limited resources, defeatist beliefs
about performance and social affiliations (which is found
to be an important mediator in the relationship between
cognitive impairment and both negative symptoms and
functioning) [32], as well as disengagement and avoid-
ance that characterize negative symptoms and result in
poor treatment outcome [33], where patients with
negative symptoms protect themselves from expected
pains and rejections associated with engagement in
constructive activity [34].
There is consistency on the link between neurocognitive
underpinning, negative symptoms, and poor outcome
with chronicity and resistance to treatment [16,29,35].
One of the interesting results of the current study is the
high significant relation between total negative PANSS
Table 5 Comparison between total positive and negative PANSS scores according to sociodemographics, clinical characteristics,
and medical and treatment history for 95 chronic schizophrenia patients
Total negative PANSS score Total positive PANSS scores
rPNM/SD rPNM/SD
Age 0.044 0.67 95 28.49 ± 10.9 0.195 0.05 95 17.8 ± 7.0
Onset age 0.028 0.79 95 28.4 ± 10.9 0.105 0.32 95 17.8 ± 7.0
Duration of illness 0.040 0.70 95 28.4 ± 10.9 0.136 0.18 95 17.8 ± 7.0
Relapse number – 0.070 0.48 95 28.4 ± 10.9 0.002 0.98 95 17.8 ± 7.0
Relapse duration 0.101 0.32 95 28.4 ± 10.9 0.0 84 0.42 95 17.8 ± 7.0
Last stay duration – 0.105 0.31 95 28.4 ± 10.9 0.045 0.66 95 17.8 ± 7.0
Total stay duration – 0.068 0.51 95 28.4 ± 10.9 0.057 0.58 95 17.8 ± 7.0
Mini-Mental State Examination – 0.320 0.001*** 95 28.4 ± 10.9 0.068 0.51 95 17.8 ± 7.0
Disorientation 0.418 0.000*** 95 28.4 ± 10.9 0.830 0.42 95 17.8 ± 7.0
Lack of attention 0.595 0.000*** 95 28.4 ± 10.9 0.072 0.48 95 17.8 ± 7.0
BMI – 0.319 0.002*** 95 28.4 ± 10.9 0.010 0.92 95 17.8 ± 7.0
Waist circumference – 0.165 0.11 95 28.4 ± 10.9 0.016 0.87 95 17.8 ± 7.0
Sex
Female 15 24.2 ± 9.8 15 17.7 ± 5.7
Male 0.109 80 29.2 ± 11.01 0.933 80 17.9 ± 7.2
Job
Jobless 69 28.2 ± 10.8 69 18.2 ± 7.01
Professional 0.900 1 26.0 ± 0.0 0.655 1 18.0 ± 0.0
Retired 25 29.2 ± 11.7 25 16.7 ± 7.0
Education
Illiterate 22 32.4 ± 10.2 22 17.0 ± 4.5
Low grade 53 27.1± 11.2 53 18.0 ± 6.8
High school 0.255 17 26.7 ± 9.8 0.46 17 20.1 ± 8.7
University 3 36.6 ± 11.3 3 16.3 ± 6.4
Socioeconomic standard
Very low 26 26.7 ± 10.8 26 15.6 ± 7.6
Low 60 28.7 ± 10.7 60 18.6 ± 6.6
Moderate 0.34 8 29.8 ± 12.8 0.32 8 19.2 ± 7.2
High moderate 1 46.0 ± 0.0 1 19.0 ± 0.0
PANNS, Positive and Negative Syndrome Scale.
Significant if Po0.05.
***Highly significant if Po0.001.
Schizophrenia-negative symptoms Al Gamal et al. 17
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
scores and lower risk of metabolic syndrome, low
incidence of diabetes, and lower BMI. This could not
be explained especially by expected lower level of
activity, where Viertio
¨et al. [36] pointed out that self-
reported as well as test-based mobility limitations and
weak muscle strength (meaning a sedentary life and poor
quality of life) for patients with schizophrenia and non
affective psychosis were linked significantly to negative
symptoms.
Also, the suggested frequent use of atypical antipsycho-
tics in these patients with higher negative scores and
greater illness severity indicated by CGI-S scores
(P= 0.00) increases the risk of obesity and leads to a
higher risk of developing metabolic disturbances. In our
results, there were lower BMI and lower incidence of
DM with higher negative PANSS scores despite illness
severity and use of antipsychotics.
This interesting finding can be explained by eliminating
other risk factors for obesity and metabolic dysregulation,
such as the poor quality of life of these patients with long
hospital stay with controlled diet, smoking, and sporting
activity, and lacking genetic predisposition for diabetes,
hypertension, and dyslipidemia (n= 25), with a negative
family history (P= 0.003); there was no such genetic
predisposition in patients who had higher negative scores.
Concept of resistant schizophrenia
For most of the researchers, the concept of treatment
resistant schizophrenia has a precise meaning; it is the
persistence of positive symptoms, which are moderate or
severe, after correct biological treatments [37]. This
definition lacks a growing awareness of the problem of
persistent negative symptoms, especially in terms of the
controversy on the efficacy of novel antipsychotics in such
groups of symptoms, so that if shown to be efficacious,
it could be because of the improvement in secondary
negative symptoms to depression, extrapyramidal symp-
toms, and psychoses, but not primary negative symp-
toms [38]. Others consider that ‘nonresistance’ also
includes complete disappearance of negative, cognitive,
and affective symptoms in addition to complete recovery
of the predisease functioning [39]. The International
Psychopharmacology Algorithm Project (IPAP) had estab-
lished criteria for treatment refractoriness, but focusing
on positive symptoms; however, the IPAP also considers
continued negative or cognitive symptoms, violence,
Table 6 Comparison between nonresistant and different resistant schizophrenia groups according to their clinical characteristics
and treatment history
Symptoms Nonresistant Kane’s resistant Negative resistant Overlap resistant Total P-value
Waist circumference
Z102#23 11 10 6 50
Z88~
94–101.9#4 6 8 1 19 0.22
84–87.9~
o94#68 8 426
o84~
Total 33 25 26 11 95
Metabolic syndrome
Normal 1 3 3 2 9
Risky 2 6 7 2 17
High risky 18 10 13 6 47 0.129
Definite 12 6 3 1 22
Total 33 25 26 11 95
Treatment category
Conventional 10 5 7 1 23
Atypical 23 20 10 10 72 0.49
Total 33 25 26 11 95
Trial 1 and treatment history
Conventional 28 19 25 9 81
Atypical 5 6 1 2 14 0.30
Total 33 25 26 11 95
Trial II and treatment history
Conventional 16 5 11 4 36
Atypical 17 20 15 7 59 0.089
Total 33 25 26 11 95
Current atypical
Clozapine 10 13 10 4 37
Olanzapine 5 2 2 0 9
Risperidone 6 4 6 3 19
Quetiapine 1 2 2 2 7
Aripiprazole 0 0 1 0 1
Significant if Po0.05.
Highly significant if Po0.001.
Table 7 Logistic Regression Model for significant predictors for
resistant negative schizophrenia of 95 cases
Resistant negative schizophrenia
= 1.804 constant
= + 0.195 ofo20 MMSE scores, OR = 1.2 (0.422–3.504)
= + 0.450 of disorientation score, OR = 1.046 (0.709–2.54)
= + 0.406 of lack of attention score, OR = 1.50 (0.941–3.391)
w
2
model = 14.051
Significance = 0.04
R
2
= 0.186
MMSE, Mini-Mental State Examination; OR, odds ratio.
18 Middle East Current Psychiatry
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
suicidality, and recurrent mood symptoms as elements of
treatment refractoriness [40].
The state of noncompliance and patient-related factors
may contaminate cases of refractoriness [41]. Also,
nonresponse to psychosocial treatments is incorporated
into the definition of schizophrenia resistance [42,43].
Commonly, treatment resistance was considered to be
roughly equivalent to chronic or frequent hospitaliza-
tion [44–49]; however, chronic hospitalization can occur
despite low levels of symptoms [50] and chronicity alone
cannot accurately predict the likelihood of response to an
antipsychotic trial [42,51].
In our study, there were 62 resistant cases [26 with
predominant negative symptoms, 25 with predominant
positive symptoms (Kane modified criteria) and 11
overlapped cases]. Only 33 cases were nonresistant,
although all had a chronic course and repeated hospita-
lization, which highlights the fact that the concept of
resistant schizophrenia requires urgent revision to avoid
heterogeneity and confusion.
In more specific words, the concept of schizophrenia
resistance is unclear and confusing; is it the treatment
resistance or the illness itself? It lacks precise nosological
criteria, and thus leads to difficult definitions, and hence,
management. Weak predictive value for environment,
social, and psychological factors, besides the absence of
specific biological findings for this group of patients, may
increase such confusion and heterogeneity.
Thepresenceofcaseswithpredominantnegativesymp-
toms (26) challenges the classical definition of treatment
resistant schizophrenia; on the other hand, the presence of
cases (33) fulfilling non resistant criteria denotes that
causes other than treatment resistance may be responsible
for chronicity and chronic institutionalization.
In attempts to create a practical definition that includes
all aspects of schizophrenia resistance (positive, negative,
cognitive, treatment refractoriness, and chronicity),
different scores of PANSS, CGI-S, treatment history,
and cognitive profile were included as follows.
In terms of the history, it required the presence of two
previous trials of antipsychotics treatment with ensured
compliance of the full therapeutic range (Z1000 mg
chlorpromazine equivalent) for a 3–6-month period, and
poor functioning for the last 2 years over the last 5 years.
In terms of the psychometric assessments, it requires the
PANSS scores to show total positive score Z16, total
negative score Z23, and total psychopathology score Z39,
and the CGI-S score Z4 and MMSE score r20. Finally,
the failure of a full trial of psychosocial treatment with all
modalities including CBT may be a suggestive criterion.
Conclusion and recommendations
Negative and cognitive symptoms are important aspects
of the definitions of resistant schizophrenia, where early
assessment and management of negative and cognitive
deficits is needed in first-episode patients. Moreover,
treatment failure should include psychological modula-
tions as well as drug refractoriness.
It is worth mentioning that the lack of differentiation
between different groups of resistant schizophrenia and
nonresistant cases in chronic patients in terms of
sociodemographic and clinical characteristics, as well as
treatment history blurs the picture and indicates hetero-
geneity, which in turn should direct the researchers
Table 8 Correlation for different resistant and nonresistant schizophrenia groups according to their clinical characteristics, age, and
MMSE scores
Nonresistant Kane’s resistant Negative resistant Overlap resistant
NM/SD NM/SD NM/SD NM/SD P-value
Age 33 49.6 ± 8.7 25 46.1 ± 11.0 26 50.4 ± 11.2 11 47.8 ± 11.1 0.45
Onset age 33 21.8 ± 6.2 25 20.7± 6.9 26 21.7 ± 3.6 11 19.09 ± 4.8 0.51
Duration of illness 33 27.5 ± 8.7 25 25.5 ± 8.9 26 28.6 ± 10.8 11 29.1 ± 8.9 0.6
Relapse number 33 19.1 ± 12.2 25 17.3 ± 8.8 26 20.1± 15.2 11 20.4 ± 14.7 0.85
Relapse duration 33 3.6 ± 1.7 25 2.2 ± 1.1 26 4.2 ± 7.08 11 3.3 ± 1.8 0.37
Last stay duration 33 10.6 ± 5.8 25 9.8 ± 7.6 26 9.2 ± 5.6 11 8.4 ± 5.3 0.71
Total stay duration 33 16.02 ± 6.5 25 14.04 ± 8.5 26 14.4± 8.02 11 12.8 ± 6.4 0.58
MMSE 33 21.7 ± 6.2 25 19.4 ± 7.1 26 16.1± 6.8 11 15.9 ± 8.9 0.05*
MMSE, Mini-Mental State Examination.
*Significant if Po0.05.
Highly significant if Po0.001.
Table 9 Predictive value and diagnostic accuracy of resistant
schizophrenia by different cutoff points of PANSS and CGI-S
scores
Criterion Sensitivity Specificity PPV NPV DA
Total positive PANSS score
Z16 62.90 42.42 67.24 37.84 55.70
Z20 45.16 57.58 66.67 35.85 49.47
Z23 30.65 84.85 79.17 39.44 49.47
Z25 41.03 82.35 84.21 37.84 53.55
Total negative PANSS score
Z20 91.99 51.52 78.08 77.27 77.89
Z23 88.71 81.82 90.16 79.41 86.32
Z25 88.71 94.12 96.49 82.05 90.63
Total general psychopathology score
Z39 59.6 75.76 82.22 50.00 65.26
Clinical Global Impression Severity Index score
Z4 98.3 36.36 74.39 92.31 76.84
CGI-S, Clinical Global Impression Severity Index; DA, diagnostic
accuracy; NPV, negative predictive value; PANNS, Positive and
Negative Syndrome Scale; PPV, positive predictive value.
Schizophrenia-negative symptoms Al Gamal et al. 19
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
toward syndrome delineation and focus on biological
differentiations.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
References
1Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease
within the syndrome of schizophrenia. Arch Gen Psychiatry 2001; 58:
165–171.
2Stahl SM, Buckley PF. Negative symptoms of schizophrenia: a problem that
will not go away. Acta Psychiatr Scand 2007; 115:4–11.
3Carpenter WT Jr, Heinrichs DW, Wagman AMI. Deficit and nondeficit forms
of schizophrenia: the concept. Am J Psychiatry 1988; 145:578–583.
4Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A,
Carpenter WT Jr. Effects of clozapine on positive and nega tive symptoms in
outpatients with schizophrenia. Am J Psychiatry 1994; 151:20–26.
5Kopelowicz A, Liberman RP, Mintz J, Zarate R. Comparison of efficacy of
social skills training for deficit and nondeficit negative symptoms in schizo-
phrenia. Am J Psychiatry 1997; 154:424–425.
6Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT. Positive and
negative symptom response to clozapine in schizophrenic patients with and
without the deficit syndrome. Am J Psychiatry 1998; 155:751–760.
7Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of recovery in
deficit syndrome schizophrenia: a 20-year multi-follow-up longitudinal study.
Schizophr Bull 2010; 36:788–799.
8Kirkpatrick B, Galderisi S. Deficit schizophrenia: an update. World Psychiatry
2008; 7:143–147.
9Ziauddeen H, Dibben C, Kipps C, Hodges JR, McKenna PJ. Negative
schizophrenic symptoms and the frontal lobe syndrome: one and the same?
Eur Arch Psychiatry Clin Neurosci 2011; 261:59–67.
10 Hong LE, Avila MT, Adami H, Elliot A, Thaker GK. Components of the smooth
pursuit function in deficit and nondeficit schizophrenia. Schizophr Res 2003;
63 (1–2): 39–48.
11 Malaspina D, Coleman E, Goetz RR, Harkavy-Friedman J, Corcoran C,
Amador X, et al. Odor identification, eye tracking and deficit syndrome
schizophrenia. Biol Psychiatry 2002; 51:809–815.
12 Fleischhacker WW. New drugs for the treatment of schizophrenic patients.
Acta Psychiatr Scand 1995; 91:24–30.
13 Lauriello J, Lenroot R, Bustillo JR. Maximizing the synergy between
pharmacotherapy and psychosocial therapies for schizophrenia. Psychiatr
Clin North Am 2003; 26:191–211.
14 Toomey R, Kremen WS, Simpson JC, Samson JA, Seidman LJ, Lyons MJ,
et al. Revisiting the factor structure for positive and negative symptoms:
evidence from a large heterogeneous group of psychiatric patients. Am J
Psychiatry 1997; 154:371–377.
15 Ratakonda S, Gorman JM, Yale SA, Amador XF. Characterization of
psychotic conditions: use of the domains of psychopathology model. Arch
Gen Psychiatry. 55; 1998. pp. 75–81.
16 Ho B-C, Nopoulos P, Flaum M, Arndt S, Andreasen NC. Two-year outcome in
first-episode schizophrenia: predictive value of symptoms for quality of life.
Am J Psychiatry 1998; 155:1196–1201.
17 El SHiekh M, Sadek A, Omar AN, El-Nahas G. Psychiatric morbidity among
the first degree relatives of a sample of children with attention deficit hy-
peractivity disorder [MD thesis]. Cairo, Egypt: Ain Shams University; 2003.
18 Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale
(PANSS) Rating Manual, Montefiore Medical Centre and Schizophrenia
Bulletin. 29 New York: Department of Psychiatry, Albert Einstein College of
Medicine; 1986. pp. 757–769.
19 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): a
comprehensive review. J Operat Psychiatry 1991; 148:472.
20 Guy W. ECDEU Assessment Manual for Psychopharmacology – Revised
(DHEW Publ No ADM 76-338). Rockville, MD, USA: Department of Health,
Education and Welfare, Public Health Service, Alcohol, Drug Abuse and
Mental Health Administration, NIM H Psychopharmacology Research
Branch, Division of Extramural Research Programs; 1976. pp. 218–222.
21 Folstein MF, Folstein SE, McHugh PR.‘Mini mental state’. A practical method
for grading the cognitive state of patients for the clinician. J Psychiatr Res
1975; 12:189–198.
22 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-re-
sistant schizophrenic. A double-blind comparison with chlorpromazine. Arch
Gen Psychiatry 1988; 45:789–796.
23 Buchanan RW, Kirkpatrick B, Heinrichs DW, Carpenter WT Jr. Clinical correlates
of the deficit syndrome of schizophrenia. Am J Psychiatry 1990; 147:290–294.
24 Lieberman J, Stroup T, McEvoy J, Swarz M, Rosenheck R, Perkins D, et al.
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
Investigators: effectiveness of antipsychotic drugs in patients with
chronic schizophrenia. N Engl J Med 2005; 353:120 9–1223.
25 Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP,
et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CON-
SIST): the efficacy of glutamatergic agents for negative symptoms and
cognitive impairments. Am J Psychiatry 2007; 164:1593–1602.
26 Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of
schizophrenia: therapeutic opportunity or Cul-de-sac? Acta Psychiatr Scand
2007; 115:93–100.
27 McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA,
et al. Effectiveness of clozapine versus olanzapine, quetiapine, and
risperidone in patients with chronic schizophrenia who did not respond
to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163
600610.
28 Rosenheck R, Dunn L, Peszke M, Cramer J, Xu W, Thomas J, Charney D.
Impact of clozapine on negative symptoms and on the deficit syndrome in
refractory schizophrenia. Am J Psychiatry 1999; 156:88–93.
29 Milev P, Ho B-C, Arndt S, Andreasen NC. Predictive values of neurocogni-
tion and negative symptoms on functional outcome in schizophrenia:
a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry
2005; 162:495–506.
30 Perivoliotis D, Cather C. Cognitive behavioral therapy of negative symptoms.
J Clin Psychol 2009; 65:815–830.
31 Shepard PD, Holcomb HH, Gold J M. The presence of absence: Habenular
regulation of dopamine neurons and the encoding of negative outcomes.
Schizophr Bull 2006; 32:417–421.
32 Grant PM, Beck AT. Defeatist beliefs as a mediator of cognitive impairment,
negative symptoms, and functioning in schizophrenia. Schizophr Bull 2009;
35:798–806.
33 Beck AT, Rector NA, Grant PM. Schizophrenia: cognitive theory: research
and therapy. New York: Guilford; 2009.
34 Mueser KT, Meyer PS, Penn DL, Clancy R, Clancy DM, Salyers MP.
The illness management and recovery program: Rationale, development, and
preliminary findings. Schizophr Bull 2006; 32 (Suppl 1): S32–S43.
35 Davidson L, McGlashan TH. The varied outcomes of schizophrenia. Can J
Psychiatry 1997; 42:34–43.
36 Viertio
¨S, Sainio P, Koskinen S, Pera
¨la
¨J, Saarni SI, Sihvonen M, et al.
Mobility limitations in persons with psychotic disorder: findings from a
population-based survey. Soc Psychiatry Psychiatr Epidemiol 2009;
44:325–332.
37 Peuskens J. The evolving definition of treatment resistance. J Clin Psychiatry
1999; 60 (Suppl 12): 4–8.
38 Meltzer HY, Burnett S, Bastani B, Ramirez LF. Effects of six months of
clozapine treatment on the quality of life of chronic schizophrenic patients.
Hosp Community Psychiatry 1990; 41:892–897.
39 Wilson WH. Reassessment of state hospital patients diagnosed with schi-
zophrenia. J Neuropsychiatry Clin Neurosci 1989; 1:394–397.
40 Ballon JS, Lieberman JA. Advances in the management of treatment-resist ant
schizophrenia. Focus 2010; 8:475–487.
41 Elkis H, Meltzer HY. Refractory schizophrenia. Revista Brasileira de Psiquiatr
2007; 29 (Suppl 2): S41–S47.
42 Brenner HD, Dencker SJ, Goldstein MJ, Hubbard JW, Keegan DL, Kruger G,
et al. Defining treatment refractoriness in schizophrenia. Schizophr Bull
1990; 16:551–561.
43 Brenner HD, Merlo MCG. Definition of therapy-resistant schizophrenia and
its assessment. Eur Psychiatry 1995; 10 (Suppl 1): 11S–17S.
44 Holden JMC, Itil TM, Keskiner A, Fixk M. Thioridazine and chlordiazepoxide,
alone and combined, in the treatment of chronic schizophrenia. Compr
Psychiatry 1968; 9:633–643.
45 Small JG, Kellams JJ, Milstein V, Moore J. A placebo controlled study of
lithium combined with neuroleptics in chronic schizophrenic patients. Am J
Psychiatry 1975; 132:1315–1317.
46 Lingjaerde O, Engstrand E, Ellingsen P. Antipsychotic effect of diazepam
when given in addition to neuroleptics in chronic psychotic patients: a
double-blind clinical trial. Curr Ther Res 1979; 26:505–514.
47 Ruskin P, Averbukh I, Belmaker RH, Dasberg H. Benzodiazepines in chronic
schizophrenia. Biol Psychiatry 1979; 14:557–558.
48 Carman JS, Bigelow LB, Wyatt RJ. Lithium combined with neuroleptics in
chronic schizophrenic and schizoaffective patients. J Clin Psychiatry 1981;
42:124–128.
49 Wolkowitz OM, Pickar D, Doran AR, Breier A, Tarell J, Paul SM . Combination
alprazolam-neuroleptic treatment of the positive and negative symptoms of
schizophrenia. Am J Psychiatry 1986; 143:85–87.
50 McGlashan TH. A selective review of recent North American long-term follow
up studies of schizophrenia. Schizophr Bull 1988; 14:515–542.
51 Christison GW, Kirch DG, Wyat RJ. When symptoms persist: choosing
among alternative somatic treatments for schizophrenia. Schizophr Bull
1991; 17:217–245.
20 Middle East Current Psychiatry
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
Schizophrenia-negative symptoms Al Gamal et al. 21
Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited.
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
The negative symptoms of schizophrenia have been considered to be a psychiatric form of the frontal lobe syndrome. However, no studies have compared these two disorders at the clinical level. In this study, 12 negative symptom schizophrenic patients and 11 patients with behavioural variant frontotemporal dementia (bv-FTD) were rated for negative symptoms and for occurrence of frontal lobe behaviours in everyday life. They were also rated for speech disorder and were given a series of executive tests. Both patient groups showed positive ratings on negative symptoms and frontal lobe behaviours in daily life; however, the schizophrenic patients had higher negative symptom scores and the bv-FTD patients had higher carer ratings on frontal behaviours in daily life. Both groups were impaired on the executive tests, but the bv-FTD patients showed significantly greater impairment on verbal fluency and a test requiring inhibition of prepotent responses. A minority of the bv-FTD patients unexpectedly showed speech abnormalities typically associated with schizophrenia. The findings indicate that the negative syndrome in schizophrenia and the frontal lobe syndrome resemble each other clinically in important respects. Some of the differences may be attributable to the additional presence of disinhibition in the frontal lobe syndrome.
Article
Full-text available
Addressing the need for research on the nature of refractoriness to antipsychotic drug therapy exhibited by a substantial minority of schizophrenic patients, Philip R.A. May and Sven Jonas Dencker instigated an international study group to discuss this problem, beginning with the International Congress of Neuropsychopharmacology in Göteborg, Sweden, in 1980. The study group subsequently met in Haar, Federal Republic of Germany, in 1985; in Banff, Canada, in 1986; and again in Telfs, Austria, in 1988. The study group set three objectives: (1) to clarify the concept of treatment resistance or refractoriness; (2) to suggest criteria for defining or rating the degree of treatment refractoriness; and (3) to explore the role of psychosocial and drug therapies in increasing the responsiveness of the treatment refractory patient. This position article represents a distillation of the study group's efforts to define treatment refractoriness in schizophrenia.
Article
Twenty-three chronic psychotic patients, mainly male schizophrenics, already on neuroleptics, were given diazepam (15 mg daily) and placebo for three weeks each, in random order. The mean total score on the Brief Psychiatric Rating Scale (BPRS) was significantly lower in the diazepam period than in the placebo period; no significant difference was found for the total score of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). A significant difference in favor of diazepam was seen for the single BPRS items 'Suspiciousness' and 'Unusual thought content'. The doctors' preference showed a non-significant trend in favor of the diazepam period. No significant prognostic factors could be identified in this small material. Dysarthria, ataxia, hypokinesia and drowsiness were the commonest side effects in the diazepam as compared to the placebo period. It is concluded that diazepam seems to enhance the antipsychotic effect of neuroleptics in chronic schizophrenic patients.
Article
Schizophrenia is a serious mental illness responsible for tremendous morbidity and decreases in quality of life and productivity. It is the eighth leading cause of disability-associated life years lost (1) and accounts for nearly 1.1% of overall losses according to the World Health Organization (2). Although there are several treatments for schizophrenia, numerous individuals continue to experience the wide range of symptoms with which many patients present. Current medications target positive symptoms, i.e., hallucinations and delusions, but are not effective for negative symptoms, i.e., apathy, social dysfunction, and flat affect, or cognitive symptoms, such as deficits in executive function and working memory.
Article
The clinical effects of thioridazine (5 mg./Kg.) and chlordiazepoxide (1 mg./Kg.) alone and combined at half strength (2.5 mg./Kg. and 0.5 mg./Kg.) in the treatment of 24 chronic schizophrenic males were observed in a fixed dosage double-blind crossover study. Eight-week treatment periods were separated by eight-week placebo periods.In global ratings, both thioridazine and the combined drug treatments were effective in twenty of the 22 subjects who completed the study. Chlordiazepoxide decreased global ratings in eleven of the 22 subjects.In psychopathological cluster scores, differences in therapeutic ranges for the treatments were observed, with the greatest number of improvement scores in disorders of affect, association, thought content, will, and mood for thioridazine and the combination. Deterioration occurred in a few instances, and these were mainly associated with chlordiazepoxide treatment.Single item analyses showed differences in the clinical efficacy of each drug alone and in combination, but there were only 15 items of psychopathology in which combined medication was superior to thioridazine treatment alone.
Article
The treatment of nonresponsive schizophrenia poses perennial problems. The situation is made yet more complex when the great variety of patient types, their social background, family circumstances and psychosocial requirements are taken into account. The comparative lack of response to neuroleptic therapy seen in some patients, especially those with minimal structural brain changes, further complicates the problem, provoking-as such therapy may-more EPS than are normally seen in patients without more obvious physical changes in brain structure. Until recently, the treatment of nonresponsive schizophrenia has tended to involve switching from one neuroleptic (usually a "highpotent" agent) to another of different chemical structure. However, as these "typical" neuroleptics occupy D(2) receptors, the rationale for using a less conventional antipsychotic, such as clozapine, is increasingly appreciated in the management of the treatment-refractory schizophrenic.