Schizophrenia Bulletin vol. 37 suppl. 2 pp.

S98–S110, 2011
doi:10.1093/schbul/sbr073

Negative Symptoms of Schizophrenia as Primary Target of Cognitive Behavioral

Therapy: Results of the Randomized Clinical TONES Study

Stefan Klingberg*,1, Wolfgang Wölwer2, Corinna Engel3, Andreas Wittorf1, Jutta Herrlich4, Christoph Meisner3,
Gerhard Buchkremer1, and Georg Wiedemann5
1
Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstrasse 24, D-72076 Tübingen, Germany; 2Department of
Psychiatry and Psychotherapy, University of Duesseldorf, Duesseldorf, Germany; 3Institute of Medical Biometry, University of Tübingen,
Tübingen, Germany; 4Department of Psychiatry and Psychotherapy, University of Frankfurt, Frankfurt, Germany; 5Department of Psychiatry
and Psychotherapy, Klinikum-Fulda, Fulda, Germany
*To whom correspondence should be addressed; tel: þ49-7071-2982330, fax: þ49-7071-294141, e-mail: stefan.klingberg@med.
uni-tuebingen.de

Clinical studies on cognitive behavioral therapy (CBT) that symptoms.1 Negative symptoms have been divided into
include schizophrenia patients primarily on the basis of primary and secondary symptoms.2,3 Negative symptoms
negative symptoms are uncommon. However, those studies are viewed as secondary if they are a result of side effects
are necessary to assess the efficacy of CBT on negative symp- of medications or are a psychological reaction to psychotic
toms. This article first gives an overview of CBT on negative symptoms or a consequence of cooccurring depressive
symptoms and discusses the methodological problems of symptoms. In the absence of these factors, negative symp-
selecting an adequate control group. Furthermore, the article toms are thought to be primary, ie, associated with the dis-
describes a clinical study (the TONES-Study, ISRCTN order itself. Negative symptoms in general are strong
25455020), which aims to investigate whether CBT is specif- predictors of a poorer prognosis, poorer social outcome,
ically efficacious for the reduction of negative symptoms. and poorer quality of life.4 Negative symptoms are present
This multicenter randomized clinical trial comparing CBT in the prodromal phase, during psychosis, and after the
with cognitive remediation (CR) for control of nonspecific remission of positive symptoms.5–7 According to meta-
effects is depicted in detail. In our trial, schizophrenia analyses, medication has only limited effects on negative
patients (n 5 198) participated in manualized individual symptoms. Leucht et al8 showed that only 4 second-
outpatient treatments. Primary outcome is the negative generation drugs were more efficacious than first-
syndrome assessed with the positive and negative syndrome generation drugs for negative symptoms with effect sizes
scale, analyzed with multilevel linear mixed models. Patients ranging between 0.13 and 0.32. In addition, the comparison
in both groups moderately improved regarding the primary of second-generation drugs with placebo results in a stan-
endpoint. However, against expectation, there was no dardized mean difference of 0.39 favoring second-genera-
difference between the groups after treatment in the intention tion drugs.9 These findings are based on studies
to treat as well as in the per-protocol analysis. In conclusion, examining patients with predominantly positive symptoms
psychotherapeutic intervention may be useful for the reduc- and do not allow concluding that second-generation drugs
tion of negative symptoms. However, there is no indication are effective for persistent negative symptoms. On this back-
for specific effects of CBT compared with CR. ground, the Measurement and Treatment Research to
Improve Cognition in Schizophrenia initiative10 aims to
Key words: schizophrenia/cognitive behavioral therapy/ develop new treatments for improving negative symptoms
cognitive remediation/negative symptoms/randomized and cognitive impairments.4
clinical trial
Efficacy of Cognitive Behavioral Therapy for Negative
Symptoms
Introduction
According to Mäkinen’s et al review,11 the effects of family
Thetreatment ofnegative symptoms isa major challenge for interventions or psychoeducation on negative symptoms
mental health care in schizophrenia. Even 1 year after the are unsatisfying. However, several reviews and meta-
last episode, up to 50% of the patients suffer from negative analyses summarized evidence for the efficacy of cognitive
Ó The Author 2011. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oup.com.

S98
 Results of the Randomized Clinical TONES Study

behavioral therapy (CBT),12–17 which led to the recommen- Cognitive Models of Negative Symptoms
dationofCBT forroutine care (RC)inevidence-based treat- The cognitive model25 of primary negative symptoms
ment guidelines. For example, Rector and Beck14 report in echoes the work of Bleuler.26 Bleuler viewed these as being
their review, 3 studies18–20 analyzing change in negative the primary symptoms of schizophrenia and suggested
symptoms. These studies that compare CBT as active treat- that they represented a defensive position in relation to
ment with RC as nonactive treatment resulted in large effect intolerable stress. Our own findings are in line with those
sizes between 0.88 and 1.19. When CBT was compared with interpretations. Wittorf et al27 found that the relationship
control group like supportive counseling, which provides between negative symptoms and specific self-concepts
similar therapeutic attention, this resulted in lower effect was consistently significant, even when the contribution
sizes for CBT ranging from 0.21 to 0.47.14 This finding indi- of depression was partialed out. According to Kingdon
cates that nonspecific control conditions have active ther- and Turkington,25 negative symptoms may in fact be
apeutic ingredients and are leading to unspecific effects on more widespread in people with high levels of vulnerability
symptoms, contrary to the older assumption that they are and a low capability to cope with stress, who often develop
therapeutically inert. Regarding negative symptoms, the social phobia, agoraphobia, and tendencies toward institu-
meta-analysis of Wykes et al16 reported a mean-weighted tionalization. In line with these assumptions, Kingdon
effect size of 0.44 for CBT based on 23 randomized clinical and Turkington,25 Beck et al,28 and Rector et al29 pro-
trials. From these 23 studies, only 2 studies targeted negative pose several cognitive therapy explanations for negative
symptoms as a primary outcome,21,22 the remaining studies symptoms. In their view, affective flattening may develop
with positive symptoms as primary outcome. Thus, the ma- from demoralization, perhaps related to past traumatic
jority of studies are specifically tailored to address positive events. Furthermore, avolition could be a result of the per-
symptoms like delusions or hallucinations and are based on ceptionofbeing under pressure andsubjecttofailing expect-
a cognitive model of psychotic symptoms. The therapeutic ations. However, there have been only few approaches to
strategies applied in those studies19,23 cover interventions systematically address negative symptoms by means of
like normalization, thought linkage, behavioral experi- manualized cognitive behavioral interventions. The treat-
ments, cognitive restructuring, and reattribution of voices ment conceptualization of Bailer et al22 focuses on symp-
to the self. Thus, as in drug trials, the primary outcome tom-management, activity scheduling, identification of
of the majority of CBT studies has been the positive syn- stressors, problem-solving training, social skills training
drome while negative symptoms were assessed as secondary (SST), relaxation techniques, and cognitive remediation
outcome measure. These studies show that patients whose (CR). According to the more current literature,29 the targets
positive symptoms have been treated show also improve- of CBT in patients with negative symptoms are generalized
mentsfor negativesymptoms. However, thereported effects expectations of failure and discomfort in social situations,
of CBT on negative symptoms in studies mainly designed to which might be associated with a lack of motivation,
address positive symptoms do not answer the question avolition, and anergia. Grant et al30 found that defeatist
whether CBT is an effective intervention for persistent neg- belief endorsements were mediators in the relationship
ative symptoms. The Wykes’ et al meta-analysis could iden- between cognitive impairment and negative symptoms. In
tify only one study22 which assessed negative symptoms as addition, Grant et al31 found that asocial beliefs but not
a primary outcome and applied individual cognitive behav- neurocognition and emotion perception are associated
ioral therapy and not group therapy or a combination of with social functioning. Reducing defeatist beliefs by means
clinical interventions. The study reported a large effect on of cognitive treatment strategies could therefore enhance
negative symptoms but has neither a randomized design patients’ activity rate. A further target are social cognitive
nor a systematic recruitment. Further the sample size was deficits regarding emotion detection, emotion expression,
very small. Finally, the latest National Institute for Health and social schemata which can be viewed as mediators be-
and Clinical Excellence (NICE) meta-analysis24 reports tween neurocognition, functioning, and negative symptoms
only small effect sizes for CBT on negative symptoms of like affective blunting as well as social and emotional
0.01 for posttreatment and of 0.31 for follow-up assess- withdrawal.32 Fosteringadequateperceptionofsocialsitua-
ments. To summarize, negative symptoms constitute tions, improving emotion detection and expression, and
a key element of overall symptoms, weakening the patients’ training of required skills are plausible targets of interven-
ability to manage everyday activities and affecting their tion for the reduction of negative symptoms.33
quality of life. The literature review shows that CBT might
have the potential to ameliorate negative symptoms of
schizophrenia disorders. However, so far there are no meth- Which Control Condition is Adequate?
odologically sound clinical trials on CBT, which address We considered several options for implementing a control
negative symptoms as a primary outcome. Based on the het- group for the CBT, which have different implications for
erogeneous findings outlined above, there is clearly a need the interpretation of results. (1) Treatment as usual
to further investigate CBT for the reduction of negative (TAU): when compared with a CBT þ TAU condition,
symptoms. TAU is a ‘‘no treatment control group’’ controlling for
S99
S. Klingberg et al.

spontaneous change of symptoms and effects of being functions are common and represent a limiting factor
in a trial. Effects of therapeutic commitment are not for the reintegration.
controlled by this control condition. Superiority of the
CBT would imply only that any treatment can improve
the course of symptoms. (2) Supportive Treatment (ST): Methods
ST controls for therapeutic commitment in addition to Design
the factors controlled for by TAU. ST conditions are
Thisstudyisarandomizedclinicaltrial(theTONES-Study,
usually viewed as a kind of placebo intervention in the
ISRCTN 25455020) with 2 parallel groups (allocation ratio
sense that specific factors of the test treatment are not
1:1), blinded assessment, conducted in 3 study centers in
addressed by this kind of control treatment. However,
Germany. After trial commencement, there were no
it is difficult to describe the content of ST. In particular,
changes to methods or outcome assessment.
this is a major problem when the treatment is conducted
over the long term. In addition, expectations from either
the patient or the therapist whether or not this is a helpful Participants
and efficacious treatment vary to a great extent but can be A systematic recruitment strategy was applied in the
responsible for different treatment effects. Finally, it is un- catchment areas of the Departments of Psychiatry
clear whether some forms of ST might be effective treat- and Psychotherapy at the Universities of Düsseldorf,
ments of negative symptoms as discussed by Penn Frankfurt, and Tübingen between April 2006 and April
et al.34 It is plausible to assume that structuring patients’ 2008. All patients with psychotic disorders of participating
schedules, having a trustworthy person to talk to, and dis- departments were screened for eligibility for study partic-
cussing day to day problems are active ingredients in ipation. Patients were initially identified on the basis of
the treatment of negative symptoms that should be clinical documentation systems and approached by their
explicitly addressed and do not represent ‘‘unspecific’’ fac- treatment team and a study research assistant for receiving
tors. Thus, a more sophisticated ‘‘ST’’ would be a kind of consent for study participation. If patients gave their con-
active control condition enhancing the number of partic- sent, the structured baseline assessment was conducted.
ipants requested. (3) SST: published effects of SST for the The inclusion criteria were (1) Schizophrenia (Diagnostic
reduction of negative symptoms indicate that SST has and Statistical Manual of Mental Disorders, Fourth Edition,
a moderate effect on negative symptoms (ES = 0.40, Kurtz [DSM-IV]) confirmed by a structured clinical interview
et al35). Thus, a study investigating differences between (SCID-I); (2) At least one moderate negative symptom
CBT and SST would require a very large sample size, which as operationalized by a modified negative syndrome
is not available under most circumstances. (4) CR: at the (MNS) factor42 of the positiveand negative syndrome scale
time of our trial application in the year 2004, CR could (PANSS), ie, a PANSS-MNS score of
10, (3) Fluent
have been viewed as a suitable control condition to CBT speaker in German language; (4) status as outpatient;
for the reduction of negative symptoms. Our search in and (5) willingness to give informed consent. Exclusion cri-
the literature has not revealed any consistent evidence teria were (1) any PANSS positive symptom (P1–P7)
6;
for efficacy of CR for the reduction of negative symp- (2) severe depression as indicated by PANSS G6
6; (3)
toms.36 Although there were studies with small samples any extrapyramidal symptom of at least moderate inten-
which showed moderate effects of CR on negative symp- sity as assessed with the Udvalg for Klinske Undersøgelser
toms,37,38 the larger studies available at that time39,40 (UKU) side effect rating scale; (4) age < 18 or > 55; (5) ver-
did not find effects. In particular, the CR to be used in bal IQ < 80 assessed by a German multiple-choice vocab-
the present study is comparable to the study of Wölwer ulary test; (6) organic brain disease; (7) diagnosis of
et al,33 which did also show no reduction of negative substance abuse or substance dependence according to
symptoms. The review of McGurk et al41 found a mean DSM-IV/SCID-I as primary clinical problem including
effect for symptom reduction of 0.28. However, no effect the intention to initiate treatment of substance abuse/
size for negative symptoms is reported.41 Nevertheless, dependence; and (8) travel time to the study center
1 hour.
the latest NICE meta-analysis24 of the effects of CR on Patients were randomized only if they gave written in-
negative symptoms demonstrated a small effect of 0.19. formed consent to participate in the study and fulfilled all
The objective of our trial described below is to analyze inclusion criteria. The study protocol was approved pos-
whether CBT is efficacious for the reduction of primary itively by the local ethics committees of each study center.
negative symptoms in a randomized, controlled, single-
blind multicenter study. In conclusion of the literature
outlined above, we chose a CR control group. To sum- Interventions
marize, CR controls for spontaneous change, for the All patients received routine psychiatric outpatient care
effect of being in a trial, and for therapeutic commitment. outside of the study including antipsychotic medication
CR is a plausible and acceptable treatment for this and regular visits with a psychiatrist. The study interven-
patient group as deficits regarding neuropsychological tion was either CBT or CR, each conducted as outpatient
S100
 Results of the Randomized Clinical TONES Study

psychological intervention of 20 sessions in a period of 9 treatment goals and achievements and at motivating the
months. participant to engage in transfer activities.
CBT applies general principles of cognitive behavior
therapy (eg, case formulation based on a cognitive model, Therapists
goal setting, discussion of cognitive processes, homework Therapists: 5 (4 female, 1 male) specifically trained clin-
assignments, role-play) for the treatment of negative ical psychologists (master’s level) conducted the super-
symptoms. Therapists have been trained to establish vised study therapies. The same therapists delivered
a supportive, nonconfrontative relationship. In the first CBT and CR. Two of the therapists were aged 20–30
treatment phase, CBT aims at developing a shared for- years and 3 were aged 30–40 years. Three of the therapist
mulation and a shared concept of treatment. This already had completed a 3-year formal training on cog-
includes discussion of symptoms, cognitive impairment, nitive behavioral therapy. The 2 younger therapists were
and subjective theories in a normalizing way, as well as in their second year of training. Three of the therapists
the role of medication and the principles of early signs were classified as ‘‘experienced’’ in conducting cognitive
management. For the second treatment phase, we con- behavioral therapy in psychotic patients, ie, they had
ceptualized 5 treatment modules addressing single nega- completed 10-50 treatments prior to the beginning of
tive symptoms: initiative/planning, social activity, the study. Two of the therapists were less experienced.
emotional participation, emotional expression, and All therapists were trained by the authors S.K. and
speech activity. These modules reflect the heterogeneity A.W. in the application of the treatment manuals prior
of negative symptoms and allow for flexibility in design- to the first therapy session.
ing individual treatment plans. For each patient, 2 of
these modules have been selected for the second treat- Assessment of Adherence to the Manual
ment phase. This selection was guided by the symptom
profile of the patient, the functional consequences of Therapists received regular supervision of consultant clin-
the symptoms, and the willingness of the patient to ical psychologists. Therapists filled in structured session
work on these symptoms and modules. Thus, the treat- reports after each session. Sessions were audiotaped if
ment manual is characterized by a high degree of flexibil- patients gave written informed consent. An independent
ity to come up to the patient’s needs and requirements. rater evaluated one randomly selected session protocol
According to Rector et al,29 cognitive bias contributes based on these audiotapes, which were available for 78
to negative symptoms, independent of positive symp- CBT patients. Regarding the categorization of sessions
toms. Specifically, the authors postulate a cognitive set as fully, partially or insufficiently adherent to the manual
characterized by low expectancies for pleasure, success, an intraclass correlation coefficient (ICC) was computed.
and acceptance, as well as the perception of limited An ICC of 0.74 (95% CI: 0.59-0.83, P < .001) indicated
resources, which contributes to the persistence of nega- sufficient reliability of the session protocols that were cho-
tive symptoms. Based on this cognitive model, our treat- sen for determining manual adherence of complete thera-
ment aims at reducing a generalized expectancy of failure pies. An individual study therapy was considered as
(defeatist beliefs) and improving social cognitive skills having been conducted according to manual if (1) a patient
like emotion detection and expression. The treatment has attended at least 14 treatment sessions, and 2 thirds of
concept of the CBT has been described in detail these sessions (2) had a duration >40 and <60 minutes, (3)
elsewhere.43,44 had made use of manualized treatment material, and (4)
The CR has been adapted from an earlier study.33 It showed at least an adequate cooperation of the patient.
applies the principles of restitution as well as compensa- These criteria were derived from the session protocols.
tion. The program follows the principles of errorless The therapeutic alliance was assessed at the end of the third,
sixth, ninth, 12th, and 15th session of the study therapies
learning, overlearning, and immediate positive feedback
using items from the ‘‘Bern Post Session Report 2000’’
(verbal), which are combined with alternative cognitive
(BPSR).45
strategies such as systematic elaboration of information,
verbalization, self-instruction, and structuring of infor- Outcome Assessment
mation. The strategies are mostly practiced during desk-
The primary endpoint is a MNS factor (PANSS-MNS,
work in a first step and are then trained by computer
PANSS items N1, N2, N3, N4, N6, G7, G16) of the
tasks of the ‘‘cognition package/CogPack.’’ Based on PANSS at the time of 12 months after inclusion. These
these principles, the program comprises 3 sections of 5 items are derived from factor analysis42 and psychopath-
sessions, which are highly structured: training of atten- ologically more homogeneous than the standard PANSS
tion, memory, and executive functions. Social or emo- negative syndrome.
tional training aspects such as facial affect recognition Additional symptom measures have been assessed as
are explicitly not part of the CR. An initial session is secondary endpoints: negative symptoms measured
used to introduce the CR and 4 session aims at reviewing with the Scale for the Assessment of Negative Symptoms
S101
S. Klingberg et al.

(SANS) and the standard negative scale of the PANSS, has been generated by the Institute for Medical Biometry
positive symptoms assessed with the standard positive using a computerized algorithm and was stored by
scale of the PANSS, depressive symptoms evaluated CenTrial. The research assistant responsible for assess-
with the Calgary Depression Rating Scale for Schizo- ments reported inclusion of new patients by fax or email
phrenia (CDSS), clinical global impression measured to CenTrial which returned the result of the randomiza-
with the Clinical Global Impression Scale (CGI), and tion only to the therapist in order to keep the assessor
symptom self ratings assessed with the Symptom Check- blind regarding the study condition. The therapist then
list (SCL-90-R). gives the information about treatment allocation to the
PANSS, SANS, CDSS, CGI, type and dosage of anti- patient.
psychotic medication, and medication compliance46 were
documented monthly; side effects (UKU) have been Blinding
assessed at baseline, 6- and 12-month follow-up. The This is a single-blind study where only the assossors are
study protocol did not regulate the medication regimen. not aware of the patients’ treatment condition. Thera-
Medication was prescribed by physicians independent of pists were not involved in assessments. The assessors
the study team. Type and dose of pharmacological inter- instructed patients not to talk about their treatment
ventions have been modified dependent on the patient’s during assessment. In case of SAE (eg, suicidality), asses-
needs during the course of study. sors and therapists should share information about
In particular in studies on severe mental illness like symptoms. However, even in these cases, therapists
schizophrenia, the investigation of negative and adverse should not disclose the patient’s treatment condition as
treatment effects is essential in order to establish high possible. The assessors filled in a blindness protocol
standards of safety. Due to the high vulnerability of these for unintended unblindings and guessed the study condi-
patients, psychotherapy might lead to overstimulation, tion of the patient after each assessment. In 6 CBT and in
increased stress level and thus to symptom exacerbation 9 CR cases, unblinding has been documented (Fisher
or relapse. The following events have been defined as se- exact test, P = .593). Among 1569 guesses (from a total
vere adverse events (SAE): (1) death caused by suicide, (2) of 1653 assessments), 951 (60.6%; 95% CI: 58.1–63.0%)
suicide attempt, (3) suicidal crisis which has been opera- were correct. Fifty percent of correct guesses are expected
tionalized as rating 2 in item 8 (explicit plan for serious by chance.
suicidal activity without suicide attempt) of the CDSS,
and (4) severe symptom exacerbation, operationalized Sample Size Calculation
as CGI item 1
6 and item 2
6. Occurrence of SAE
have been assessed and documented regularly in monthly We calculated the sample size based on the findings of
intervals as part of the follow-up examination. Klingberg et al.47 Regarding negative symptoms, we found
an effect size of 0.41 (posttreatment difference between
Interrater Reliability a mean of 1.70 for TAU and a mean of 1.35 for CBT group
The 4 raters were psychologist or physicians with at least with a pooled SD of 0.85) which is similar to a 0.40 effect
1 year of clinical experience in the treatment of patients reported by Wykes et al16 for the reduction of negative
with psychotic disorders. The raters were trained by the symptoms by individual CBT. As software for sample
author A.W. prior to the beginning of the study. This size calculation for the analysis of longitudinal data using
training included the discussion and rating of video- multilevel mixed models is not available, we calculated the
based PANSS interviews. Afterward, 3 video-based sample size for classical ANOVA using nQuery 4.0. For
PANSS interviews, which were not part of the training, alpha .05 and beta .20, a sample size of 74 in each group
were than independently assessed by the 4 raters and sub- will be required. In order to compensate for a loss to
jected to the reliability analysis. For the PANSS-MNS, follow-up of 25%, we decided to include 2 3 99 patients.
the ICC for the interrater reliability was estimated using With a sample size of 198 individuals (99 each therapy
a SAS-Macro. The ICCs were 0.92 (95% CI: 0.56–1.00) group), 12 assessments per patient, one primary analysis
before beginning of the study (4 raters included), 0.93 variable (therapy), and one covariable (center), the power
(95% CI: 0.62–1.00) after 1 year (same 4 raters included), for a Mixed Models should be sufficient.
and 0.92 (95% CI: 0.63–1.00) at the final assessment (one
additional rater). In order to control for intrarater shift Data Management and Quality Assurance
over time, we computed ICC for each rater over time and A good clinical practice (GCP) compliant electronic case
found an average ICC for all raters of 0.98 (95% CI: report form with remote data entry was used (www.koor-
0.86–1.00). dobas.de; Institute of Medical Biometry, University of
Tübingen). CenTrial (a trial supporting company of
Randomization the Medical Faculty, University of Tübingen) took re-
A permuted block design with random blocks stratified sponsibility for on site monitoring. Each study center
by study center has been applied. The allocation sequence was visited 8 times. The monitoring focused on the
S102
 Results of the Randomized Clinical TONES Study

process of obtaining informed consent, on diagnostic and the therapeutic alliance scale of the BPSR as the depen-
procedures, the completeness of assessments, and on ap- dent variable revealed no significant time 3 study center 3
propriate documentation of adverse events. Whenever treatment condition interaction (F8, 224 = 0.692, P = .698).
possible, source data verification was applied. Assess- Furthermore, there were no significant main effects for the
ments were regarded as valid only if visits have been con- factors time (P = .962), study center (P = .146), and treat-
ducted within a time frame of 61 week of the scheduled ment condition (P = .578). This rmANOVA was based on
point in time. The database was closed for the final anal- the 70 CBT and the 50 CR patients who completed the
ysis on June 23, 2009. BPSR therapeutic alliance items at the end of session
3, 6, 9, 12, and 15.
Statistical Methods
The statistical analysis was carried out according to a pre- Medication
established analysis plan. The intention-to-treat sample At randomization, all patients were on antipsychotic
includes all randomized patients. The per-protocol popu- medication. In the first 6 months after inclusion, 96
lation includes only those randomized patients who have CBT patients and 91 CR patients still accepted any an-
still been available at the 11- or 12-month assessment and tipsychotic medication. Between the seventh and the 12th
who where regarded as treatment completer. month, 90/99 (91%) accepted antipsychotic medication in
The primary endpoint analysis was conducted with the CBT group and 80/99 (81%) in the CR group. These
linear mixed models (LMMs) using the intercept and differences are not significant (Fisher’s exact test, P =
assessments as random effects. The final models were .213 and P = .065). The cumulated median chlorproma-
optimized by defining the covariance structure via assess- zine equivalence doses49 up to the 12-month assessment
ments as repeated effects. SAS ‘‘Proc-Mixed’’ with 2-sided were 137 600 in the CBT and 135 400 in the CR (P = .785,
significance tests were used for all analyses. Hedge’s g were Wilcoxon-Test). Sixty-six CBT and 72 CR patients re-
estimated from the LMM according to Feingold.48 Only ceived antidepressant medication at randomization.
the primary endpoint was subjected to confirmatory The proportion of patients with favorable or adequate
analysis. Secondary endpoints were analyzed using stan- medication compliance in the CBT was 94/99 between
dard ANCOVAs and will be interpreted as exploratory. month 2 and 6 and 90/99 between month 7 and 12. In
the CR, the proportions were 88/99 and 81/99 (Fisher’s
Results exact tests, P = .238 and .117). The number of patients
reporting at least moderate side effects of medication
Participant Flow was 54/99 (6-month assessment) and 61/99 (12-month as-
One thousand six hundred and forty-nine patients with sessment) in the CR and 64/99 and 72/99 in the CBT
a potential diagnosis of schizophrenia were identified by (Fisher’s exact test, P = .353 and P = .509).
the systematic recruitment strategy and assessed with
regard to the inclusion criteria (figure 1). 198 (12% of Adverse Events
the screened population) gave written informed consent Twenty-three adverse events (12 CBT, 11 CR) were ob-
and fulfilled all inclusion criteria. served in 15 patients (10 CBT, 5 CR, P = 0.31, Hazard
ratio = 2.02, 95% CI: = 0.69–5.90). One CBT patient
Baseline Data died after aspiration due to vomiting which was regarded
Table 1 shows the sample description at randomization. as accident and not as adverse event of treatment. Details
In order to control for the success of the randomization, regarding adverse events will be published elsewhere.
we analyzed the differences between the study conditions.
There were no significant differences between the groups. Outcomes
Figure 2 and table 2 report the major result of this study.
Study Treatment Ninety of 99 CBT patients and 79 of 99 CR patients
In the CBT, a mean of 16.6 sessions have been conducted (Fisher exact test, P = .05) were available at the 11- or
with mean duration of 51.8 minutes; in the CR, 13.7 ses- 12-month assessment.
sions with 47.5 minutes duration. 1329 CBT sessions and LMM for the primary endpoint (Intention To Treat
1044 CR sessions were audiotaped. In the CBT, 74 analysis, ITT): the model assumes identical intercepts
patients received treatment according to the manual; in (estimated baseline values) for all patients of the same
the CR, 57 (fisher exact test, P = .024, see figure 1). center based on random allocation. Patients of center 2
The mean alliance scores across the sessions ranged be- had the lowest values for the negative syndrome (mean
tween 1.3 and 1.9 on a 3 to 3 scale for the CBT and the item score 2.83) at the start of the study, followed by center
CR condition respectively. A repeated measurement 1 (2.98, difference to center 1: 0.15) and center 3 (3.06, dif-
analysis of variance (rmANOVA) with the 3 study centers ference to center 1: 0.23). The interaction between center
and the 2 treatment conditions as between-subject factors and therapy was strong (figure 2). Only center 3 reached
S103
S. Klingberg et al.

Fig. 1. CONSORT flow chart.

the expected superiority of the CBT with 0.35 points less at (all baseline characteristics as listed in table 1) and time-
the end of the study compared with CR. In center 1, there varying effects (course of symptoms, therapeutic alliance,
was nearly no difference between the 2 treatments. In cen- number of sessions conducted) were analyzed but no indi-
ter 2, a superiority of CR of 0.36 points over CBT was ob- cation for moderation effects could be found.
served. The pre-post effect sizes in the total sample Seventy-four of 99 CBT patients and 56 of 99 CR
were 0.42 (95% CI: 0.70 to 0.13) for the CBT and patients were available for the per-protocol analysis
0.53 (95% CI: 0.82 to 0.25) for the CR condition. (Fisher exact test, P = .01) which confirms the overall
In order to investigate factors that might be associated results of the ITT-analysis. The negative symptom score
with the differences between the centers, several fixed decreased in both groups without significant difference
S104
 Results of the Randomized Clinical TONES Study

Table 1. Sample Description

Statistic Total Sample CBT CR Test (2-Tailed) P

N 198 99 99
Anamnestic information
Age (y) at study inclusion Mean (SD) 36.9 (9.9) 37.6 (9.8) 36.2 (10.0) t test .32
Age (y) at first hospitalizationa Mean (SD) 24.4 (8.9) 24.5 (8.7) 24.3 (9.1) t test .87
Gender (female) % 43.9 41.4 46.5 Fishers exact test .57
First hospitalization % 4.5 4.0 5.1 Fishers exact test 1.00
Number of previous hospitalizations Median (range) 3 (0-48) 3 (0-48) 3 (0-47) U testb .65
Mother and/or father with % 8.1 9.1 7.1 Fishers exact test .79
schizophreniaa
Diagnosis (according to DSM-IV/SCID I)
Schizophrenia, paranoid type % 60.1 58.6 61.6 Fishers exact test .77
Schizophrenia, residual type % 31.8 33.3 30.3 Fishers exact test .76
Schizophrenia, other types % 8.1 8.1 8.1 Fishers exact test 1.00
Comorbidity Axis I (according % 15.7 16.7 15.2 Fishers exact test 1.00
to DSM-IV/SCID-I)
Symptoms
Global assessment of functioning Mean (SD) 59.2 (8.8) 59.3 (9.6) 59.2 (7.9) t test .96
scale (GAF)
Positive and negative syndrome
scale (PANSS)
Modified negative syndrome Mean (SD) 3.0 (0.8) 3.1 (0.8) 3.0 (0.7) t-test .50
score (PANSS-MNS)
Positive syndrome Mean (SD) 1.5 (0.4) 1.5 (0.4) 1.5 (0.4) t test .92
(standard scale P1–P7)
Negative syndrome (standard Mean (SD) 2.6 (0.7) 2.7 (0.7) 2.6 (0.7) t test .82
scale N1–N7)
General psychopathology (standard Mean (SD) 1.9 (0.5) 1.9 (0.4) 1.9 (0.5) t test .66
scale G1–G16)
Persistence of negative % 84.9 86.9 82.8 Fishers exact test .82
symptoms >6 mo
Symptom checklist Mean (SD) 0.9 (0.6) 1.0 (0.7) 0.9 (0.5) t test .25
SCL-90-R, GSI
Verbal-IQ (MWT-B) Mean (SD) 107.6 (15.8) 106.1 (15.8) 109.2 (16.2) t test .18
Medication
Dose of antipsychotic medication Mean (SD) 543 (400) 525 (333) 561 (460) U test .74
(converted to mg chlorpromazine)
Medication-compliance (% favorable) % 88.7 91.8 85.6. Fishers exact test .18
Social situation
Occupation
Employed, without support % 24.2 24.2 24.2 Fishers exact test 1.00
Supported employment/unemployed/ % 75.8 75.8 75.8
housewife
Financial support
None % 21.2 24.2 18.2 Fishers exact test .44
Supported by family or government % 78.3 74.8 81.8
Living condition
Unsupported % 68.2 67.7 68.7 Fishers exact test .72
Supported (by family/supported % 22.7 20.2 25.3
housing)
Social contact
Frequent contacts (once a % 44.4 42.4 46.5 Fishers exact test .22
week or more)
Rare contacts (less than once a week) % 55.6 57.6 53.5
Relatives
Rare contacts (less than weekly/no % 9.1 9.1 9.1 Fishers exact test .88
relatives)
With contact (once a week or more) % 90.9 90.9 90.9

Note: CBT, Cognitive behavioral therapy; CR, Cognitive remediation; DSM-IV, Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition; SCID, Structured clinical interview for DSM-IV; GSI, Global severity index; MWT-B, Multiple-choice
vocabulary test.
a
More than 10% missing values.
b
U test has been computed because of not normal distribution.
S105
S. Klingberg et al.

Fig. 2. Multilevel linear mixed model for the primary endpoint: estimated course of negative symptoms (positive and negative syndrome
scale-Modified negative syndrome [PANSS-MNS]) from baseline (assessment 0) over 10 monthly ratings to 1-year follow-up (assessment 11)
for Cognitive behavioral therapy (CBT) and Cognitive remediation (CR) stratified for centers.

posttreatment (estimated baseline value: 2.97 decreasing to hospital within the 1-year treatment phase. This differ-
to 2.553 at 12 mo in CR and 2.57 at 12 mo in CBT, P = ence is not significant (Logrank-test, P = .390)
.905). The center effect was observed again.
Table 3 gives an overview over the analysis on the sec-
Discussion
ondary endpoints. For each variable, ANCOVA has been
computed. There was no significant difference between The efficacy of CBT for the reduction of negative symp-
the study groups regarding the secondary endpoints. toms is analyzed in this RCT using rigorous methodology:
Rehospitalization: 28 CBT patients (29.5%, SE 4.7) randomized multicenter design, systematic recruitment,
and 31 CR patients (35.1%, SE 5.1) have been readmitted adequate statistical power, blind assessments which are

Table 2. Multilevel Linear Mixed Model for the Primary Endpoint (PANSS-MNS), Analysis of Study Condition and Treatment Center

Estimated at Estimated Estimated Difference Estimated Effect size 95% CI for

Center Therapy n Baseline Slopea at 12 mo (CBT-CR) at 12 mo P of CBT vs CR at 12 mo Effect Size

1 CR 33 2.98 0.090 2.00 0.12 .39 0.17 0.31–0.65

CBT 33 2.98 0.078 2.12
2 CR 33 2.83 0.024 2.57 0.36 .02 0.43 0.92–0.06
CBT 33 2.83 0.009 2.94
3 CR 33 3.06 0.009 2.97 0.35 .02 0.45 0.03–0.94
CBT 33 3.06 0.040 2.62
Overall CR 99 2.97 0.045 2.48 0.090 .36 0.12 0.16–0.40
CBT 99 2.97 0.037 2.57

Note: CBT, Cognitive behavioral treatment; CR, Cognitive remediation; PANSS, positive and negative syndrome scale; MNS,
Modified negative syndrome.
a
Estimated difference per month.

S106
 Results of the Randomized Clinical TONES Study

controlled for rater shift, audio recording of treatment ses-

198
198
198
198
198
198
198
198
198
198
197
198
187

symptoms; CDSS, Calgary Depression Rating Scale for Schizophrenia; CGI, Clinical global impression; GAF, Global assessment of functioning; SCL, Symptom Checklist.
n
sions, manualized treatment, data monitoring by an exter-
nal institution, external statistician, and statistical analysis
.500
.642
.950
0.263
0.862
0.812
0.608
0.350
0.758
0.499
0.166
0.144
0.053

Note: CBT, Cognitive behavioural therapy; CR, Cognitive remediation; PANSS, Positive and negative syndrome scale; SANS, Scale for the assessment of negative
withadequatehandlingof missing data.The study hasbeen
Pb

conducted according to GCP standards of the Interna-

tional Conference on Harmonisation whenever applicable
0.19)
0.34)
0.25)
0.32)
0.25)
0.34)
0.30)
0.19)
0.25)
0.33)
0.21)
0.45)
0.54)
Table 3. Analysis of Secondary Endpoints, ANCOVAs Comparing Post Treatment Values Between Groups Controlling for Baseline Value and Study Center

in a psychotherapy trial.
to
to
to
to
to
to
to
to
to
to
to
to
to
Since patients with severe positive and depressive
(0.37
(0.21
(0.31
(0.24
(0.31
(0.22
(0.26
(0.36
(0.31
(0.23
(0.34
(0.11
(0.03
symptoms and with moderate extrapyramidal symptoms
Effect sizea

were excluded from the study, we can conclude that the

(95% CI)

majority of patients have primary negative symptoms.3

0.09
0.07
0.02
0.04
0.03
0.06
0.02
0.08
0.03
0.05
0.06
0.17
0.26
With mean PANSS scores of 3.0 for the MNS (2.6 for
the standard negative factor) and 1.5 for the positive syn-
drome, this sample represents an outpatient population
0.27)

0.09)
0.22)

0.11)
0.19)
–0.03)
0.37)

0.00)

0.21)
0.09)

0.15)
0.48)
0.02)
with moderate negative symptoms and rather mild pos-
itive symptoms. In addition, more than 80% of the
to
to
to
to
to
to
to
to
to
to
to
to
to

patients present with these symptoms for more than 6

(0.19
(0.84
(0.56
(0.66
(0.79
(0.59
(0.34
(0.47
(0.67
(0.75
(0.41
(0.08
(0.55
d (95% CI)

months. Two studies even on inpatients report lower scores

for negative symptoms (negative symptoms mean score:
1.96, Bechdolf et al50; 2.5: Valmaggia et al51). In CR studies,
0.09
0.59
0.28
0.37
0.50
0.31
0.07
0.18
0.39
0.46
0.13
0.20
0.26

the mean score on the PANSS Negative Syndrome Scale

d

ranged from 2.0 to 2.5 for the CR and the unspecific or

TAU condition (Lindenmayer et al52, McGurk et al53,
(11.3)
(0.7)
(0.7)
(0.5)
(1.0)
(1.0)
(0.9)
(1.0)
(1.2)
(0.7)
(0.4)
(1.0)

(0.6)

Penades et al54). Thus, the sample characteristics are

Post

1.6
2.3
1.8
2.0
0.9
1.9
2.6
1.3
1.8
0.2
3.9
61.2
0.7

adequate for a clinical trial on negative symptoms and

clearlydifferentfromthose ofstudiesonpositive symptoms.
We found an attrition rate regarding follow-up participa-
(0.4)
(0.7)
(0.5)
(0.9)
(1.0)
(0.8)
(1.0)
(1.1)
(0.6)
(0.4)
(0.8)
(7.9)
(0.5)

tion of 9% in CBT and 20% in CR. CBT showed a signifi-

cantly lower attrition. Attrition rates in methodologically
1.5
2.6
1.9
2.4
1.4
2.2
2.6
1.5
2.0
0.4
4.1
59.2
0.9
CR
Pre

well-designed studies according to Wykes et al16 lay

between 3.9% over 5 weeks (Lewis et al55) and 27.2% for
(0.76 to 0.19)

(0.73 to 0.16)

(0.63 to 0.07)
(0.68 to 0.12)
(0.65 to 0.09)
(0.65 to 0.09)
(0.59 to –0.03)

3 months (Tarrier et al56) for the CBT. In CR studies (Wykes

(0.27 to 0.29)

(0.47 to 0.09)

(0.52 to 0.04)
(0.45 to 0.11)

(0.40 to 0.16)
(0.07 to 0.63)

et al57; Reeder et al58), attrition rates at posttreatment for

Effect size of the CBT compared with CR at posttreatment assessment.

the CR condition were in a range from 9.3% over 3 months

(Wykes etal57) and20.0% over4 months.54 Interpretationof
d (95% CI)

attrition should account for the fact that in Germany all

patients have unrestricted access to psychiatric care (includ-
0.01
0.47
0.31
0.19
0.44
0.24
0.17
0.35
0.40
0.37
0.37
0.35
0.12

ing psychotherapy) outside of studies.

c

Similar to attrition, the extent of treatment participation

was different between the groups. 42% of CR patients as
(12.1)
(0.5)
(0.8)
(0.4)
(1.1)
(0.9)
(1.1)
(1.1)
(1.1)
(0.8)
(0.4)
(0.9)

(0.7)

opposed to only 25% of CBT patients attended less than

14 sessions. For CBT, these rates are comparable to Garety
Post

1.5
2.3
1.8
2.1
0.9
2.0
2.6
1.2
1.7
0.2
3.9
63.1
0.9

et al59 who reported a rate of 65%–70%of patients receiving

at least 12 of 20 sessions.
(0.4)
(0.7)
(0.4)
(0.9)
(1.0)
(1.0)
(1.0)
(1.0)
(0.6)
(0.4)
(0.8)
(9.6)
(0.7)

The major objective was to analyze whether CBT has

specific effects on negative symptoms when compared
CBT

1.5
2.7
1.9
2.3
1.3
2.2
2.8
1.6
2.0
0.4
4.2
59.3
1.0
Pre

with CR which is similar regarding therapeutic attention

Pre-post effect size of CBT.
Pre-post effect size of CR.

but whichis different regarding the postulated mechanisms

SANS affective blunting

Result of ANCOVA’s.

of change. The major result is that there was no significant

difference regarding negative symptoms between the
SANS anhedonia

groups. This is against the hypothesis of specific effects

PANSS negative

SCL-90-R—GSI
PANSS positive

SANS attention
PANSS general

CGI—severity

of CBT. This result is unbiased regarding the course of

SANS apathy
SANS alogia

SANS total
CDSS total

the therapeutic alliance, adherence to medication, dose

of medication, change of rater’s standards over time,
GAF

and the baseline parameters. A possible explanation for

the major finding is based on the assumption that patients
b

d
a

S107
S. Klingberg et al.

with negative symptoms are characterized by low expect- mechanisms of change. Therefore, the question whether
ations of pleasure, success, and social acceptance. It could the same mechanisms of change were active in both condi-
be the case that both interventions helped patients to expe- tions remains open. Furthermore, the generalizability of
rience pleasure and success, which could lead to decreased the results is restricted since patients showed only moder-
negative symptoms. Questionnaire data about self-con- ate negative symptoms, had at least a minimum of social
cepts before and after the treatment are available in this contacts, were compliant with their medication regimen,
study and will be reported elsewhere in order to and were in general cooperative. Accordingly, the results
empirically investigate this speculation. might be generalized primarily to outpatients who ask for
Patients in both groups showed improvements of treatment by themselves.
negative symptoms over time. The within-group effect In conclusion, an important question for further stud-
size of 0.49 in the CBT group meets the expectation ies is whether a combination of CBT and CR strategies
as described in the power calculation. These effect sizes might be even more effective for the treatment of patients
are similar to those of CBT for persistent positive symp- with negative symptoms.
toms (ES = 0.37, Wykes et al16), SST (ES = 0.40, Kurtz
et al35) for negative symptoms, and second-generation
Funding
antipsychotic medication for the reduction of negative
symptoms (ES = 0.39, Leucht et al9). Thus, in general, This study was funded publicly by the German Research
the effect of CBT meets the expectation. Even if this effect Foundation (Deutsche Forschungsgemeinschaft, grants
size should be considered moderate it seems to be relevant Kl 1179/2-1 and Kl 1179/3-1).
for the reduction of negative symptoms and indicates that
even chronic symptoms can be improved over time. CR
Acknowledgments
showed an even higher effect of 0.53 which was against
our expectation based on previous research. Based on the We thank Johannes Harbort, Michael Ruch, Hanna
Cochrane meta-analysis of McGrath and Hayes60 and Smoltczyk, Maria Weickert for their contribution as
own negative results on CR for the reduction of negative study raters, Klaus Hesse, Sabine Kossow, Maria
symptoms,33 we hypothesized in the planning phase of Memmou for their contribution as study therapists,
this trial that CR should have no effect on negative symp- Birgit Conradt for her contribution as supervisor,
toms. According to recent literature, it has to be expected Nicole Frommann for her contribution to the treatment
that CR should result in small effects. Pfammatter et al61 manuals, and Ute E. Jakobi-Malterre for writing
summarized a number of meta-analyses on CR and found assistance. The authors declare that there is no conflict
an effect size of 0.24 for the reduction of negative symp- of interest regarding this article.
toms. McGurk et al41 found an ES of 0.28 for the reduc-
tion of the overall symptomatology. Twamley et al62
References
emphasized that there is a huge heterogeneity regarding
patient characteristics, treatment modalities, assess- 1. Häfner H, an der Heiden W. The course of schizophrenia in
ments, and further methodological aspects which limits the light of modern follow-up studies: the ABC and WHO
the possibility of aggregate analyses. Thus, the CR studies. Eur Arch Psychiatry Clin Neurosci. 1999;249(suppl
4):14–26.
pre-post effect size of 0.53 in this study exceeds the
2. Carpenter WT, Heinrichs DW, Wagman AM. Deficit and
expectations even based on current evidence. This finding nondeficit forms of schizophrenia: the concept. Am J Psychi-
may be due to the intensive care patients received during atry. 1988;145:578–583.
study participation. The participation in monthly assess- 3. Peralta V, Cuesta MJ. Clinical models of schizophrenia: a crit-
ments may well improve the effects of study treatments. ical approach to competing conceptions. Psychopathology.
This consideration applies also on our CBT, which would 2000;33:252–258.
result in a somewhat lower ‘‘real’’ effect size than 0.42. 4. Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR. The
The study design does not allow differentiating between NIMH-MATRICS consensus statement on negative symp-
toms. Schizophr Bull. 2006;32:214–219.
the courses under TAU and the effect of psychotherapeu-
5. Lencz T, Smith CW, Auther A, Correll CU, Cornblatt B.
tic attention in both interventions. For this purpose, Nonspecific and attenuated negative symptoms in patients
a third study condition had been required which was at clinical high-risk for schizophrenia. Schizophr Res.
not included for methodological reasons, in particular 2004;68:37–48.
statistical power and the feasibility of recruitment. 6. Mason O, Startup M, Halpin S, Schall U, Conrad A, Carr V.
The present study has several limitations. First, the Risk factors for transition to first episode psychosis among
attrition rate and the rate of patients not treated according individuals with ‘at-risk mental states’. Schizophr Res.
2004;71:227–237.
to manual were significantly higher in the CR control con-
7. Thorup A, Petersen L, Jeppesen P, et al. Integrated treatment
dition. Thus, if there were a dose-response relationship ameliorates negative symptoms in first episode psychosis–
in CR, the effect of CR would have been underestimated. results from the Danish OPUS trial. Schizophr Res.
Second, the present RCT does not address the underlying 2005;79:95–105.

S108
 Results of the Randomized Clinical TONES Study

8. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. 27. Wittorf A, Wiedemann G, Buchkremer G, Klingberg S. Qual-
Second-generation versus first-generation antipsychotic drugs ity and correlates of specific self-esteem at the beginning sta-
for schizophrenia: a meta-analysis. Lancet. 2009;373:31–41. bilisation phase of schizophrenia. Psychiatry Res.
9. Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How 2010;179:130–138.
effective are second-generation antipsychotic drugs? A meta- 28. Beck AT, Rector NA, Stolar N, Grant PM. Schizophrenia.
analysis of placebo-controlled trials. Mol Psychiatry. Cognitive Theory, Research, and Therapy. New York, NY:
2009;14:429–447. The Guildford Press; 2009.
10. Green MF, Nuechterlein KH. The MATRICS initiative: de- 29. Rector NA, Beck AT, Stolar N. The negative symptoms of
veloping a consensus cognitive battery for clinical trials. schizophrenia: a cognitive perspective. Can J Psychiatry.
Schizophr Res. 2004;72:1–3. 2005;50:247–257.
11. Mäkinen J, Miettunen J, Isohanni M, Koponen H. Negative 30. Grant PM, Beck AT. Defeatist beliefs as a mediator of cogni-
symptoms in schizophrenia—a review. Nord J Psychiatry. tive impairment, negative symptoms, and functioning in
2008;62:334–341. schizophrenia. Schizophr Bull. 2009;35:798–806.
12. Gould RA, Mueser KT, Bolton E, Mays V, Goff D. Cogni- 31. Grant PM, Beck AT. Asocial beliefs as predictors of asocial
tive therapy for psychosis in schizophrenia: an effect size anal- behavior in schizophrenia. Psychiatry Res. 2010;177:65–70.
ysis. Schizophr Res. 2001;48:335–342. 32. Green MF, Nuechterlein KH. Should Schizophrenia be treated
13. Pilling S, Bebbington P, Kuipers E, et al. Psychological treat- as a neurocognitive disorder? Schizophr Bull. 1999;25:309–318.
ments in schizophrenia: I. Meta-analysis of family interven- 33. Wolwer W, Frommann N, Halfmann S, Piaszek A, Streit M,
tion and cognitive behaviour therapy. Psychol Med.
Gaebel W. Remediation of impairments in facial affect recog-
2002;32:763–782.
nition in schizophrenia: efficacy and specificity of a new train-
14. Rector NA, Beck AT. Cognitive behavioral therapy for ing program. Schizophr Res. 2005;80:295–303.
schizophrenia: an empirical review. J Nerv Ment Dis.
34. Penn DL, Mueser KT, Tarrier N, et al. Supportive therapy
2001;189:278–287.
for schizophrenia: possible mechanisms and implications for
15. Tarrier N, Wykes T. Is there evidence that cognitive behaviour adjunctive psychosocial treatments. Schizophr Bull.
therapy is an effective treatment for schizophrenia? A cautious 2004;30:101–112.
or cautionary tale? Behav Res Ther. 2004;42:1377–1401.
35. Kurtz MM, Mueser KT. A meta-analysis of controlled re-
16. Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior search on social skills training for schizophrenia. J Consult
therapy for schizophrenia: effect sizes, clinical models, and Clin Psychol. 2008;76:491–504.
methodological rigor. Schizophr Bull. 2008;34:523–537.
36. Hayes RL, McGrath J. Cognitive Rehabilitation for People
17. Zimmermann G, Favrod J, Trieu VH, Pomini V. The effect of
With Schizophrenia and Related Conditions (Cochrane Re-
cognitive behavioral treatment on the positive symptoms of
view). Oxford, UK: The Cochrane Library, Issue 1, Update
schizophrenia spectrum disorders: a meta-analysis. Schizophr
Software; 2003.
Res. 2005;77:1–9.
37. Bellucci DM, Glaberman K, Haslam N. Computer-assisted
18. Pinto A, La Pia S, Mennella R, Giorgio D, DeSimone L.
cognitive rehabilitation reduces negative symptoms in the se-
Cognitive-behavioral therapy and clozapine for clients with
treatment-refractory schizophrenia. Psychiatr Serv. verely mentally ill. Schizophr Res. 2003;59:225–232.
1999;50:901–904. 38. Velligan DI, Bow-Thomas CC, Huntzinger C, et al. Random-
19. Sensky T, Turkington D, Kingdon D, et al. A randomized ized controlled trial of the use of compensatory strategies to
controlled trial of cognitive-behavioral therapy for persistent enhance adaptive functioning in outpatients with schizophre-
symptoms in schizophrenia resistant to medication. Arch Gen nia. Am J Psychiatry. 2000;157:1317–1323.
Psychiatry. 2000;57:165–172. 39. Medalia A, Revheim N, Casey M. Remediation of memory
20. Tarrier N, Yusupoff L, Kinney C, et al. Randomised con- disorders in schizophrenia. Psychol Med. 2000;30:1451–1459.
trolled trial of intensive cognitive behaviour therapy for 40. Spaulding WD, Reed D, Sullivan M, Richardson C, Weiler
patients with chronic schizophrenia. BMJ. 1998;317:303–307. M. Effects of cognitive treatment in psychiatric rehabilitation.
21. Daniels LA. group cognitive-behavioral and process-oriented Schizophr Bull. 1999;25:657–676.
approach to treating the social impairment and negative 41. McGurk SR, Twamley EW, Sitzer DI, McHugo GJ, Mueser
symptoms associated with chronic mental illness. J Psy- KT. A meta-analysis of cognitive remediation in schizophre-
chother Pract Res. 1998;7:167–176. nia. Am J Psychiatry. 2007;164:1791–1802.
22. Bailer J, Takats I, Westermeier C. Die Wirksamkeit individu- 42. Klingberg S, Wittorf A, Wiedemann G. Disorganization and
alisierter Kognitiver Verhaltens therapie bei schizophrener cognitive impairment in schizophrenia: independent symptom
Negativsymptomatik und sozialer Behinderung: Eine kon- dimensions? Eur Arch Psychiatry Clin Neurosci.
trollierte Studie. Z Klin Psychol Psychother. 2001;30:268–278. 2006;256:532–540.
23. Cather C. Functional cognitive-behavioural therapy: a brief, 43. Klingberg S, Hesse K, Herrlich J, et al. Cognitive behavioral
individual treatment for functional impairments resulting therapy on negative symptoms of schizophrenia disorders—back-
from psychotic symptoms in schizophrenia. Can J Psychiatry. ground and therapy of the TONES-study. Nervenheilkunde.
2005;50:258–263. 2008;27:997–1006.
24. NICE.The Guidelines Manual.London, UK: NICE. Available 44. Klingberg S, Wittorf A, Herrlich J, et al. Cognitive behaviou-
at:www.nice.org.uk; 2010. ral treatment of negative symptoms in schizophrenia patients:
25. Kingdon D, Turkington D. Cognitive Therapy of Schizophre- study design of the TONES study, feasibility and safety of
nia. New York, NY: The Guilford Press; 2005. treatment. Eur Arch Psychiatry Clin Neurosci.
26. Bleuler E. Dementia praecox oder Gruppe der Schizophre- 2009;259:149–154.
nien. In: Aschaffenburg G, ed. Handbuch der Psychiatrie. 45. Fluckiger C, Regli D, Zwahlen D, Hostettler S, Caspar F.
Leipzig, Germany: Franz Deuticke; 1911. The bern post session report 2000, patient and therapist

S109
S. Klingberg et al.

versions: measuring psychotherapeutic processes. Z Klin Psy- 54. Penades R, Catalan R, Salamero M, et al. Cognitive remedi-
chol Psychother. 2010;39:71–79. ation therapy for outpatients with chronic schizophrenia:
46. Kemp R, David A. Psychological predictors of insight and a controlled and randomized study. Schizophr Res.
compliance in psychotic patients. Br J Psychiatry. 2006;87:323–331.
1996;169:444–450. 55. Lewis S, Tarrier N, Haddock G, et al. Randomised controlled
47. Klingberg S, Wittorf A, Fischer A, Jakob-Deters K, trial of cognitive-behavioural therapy in early schizophrenia:
Buchkremer G, Wiedemann G. Evaluation of a cognitive acute-phase outcomes. Br J Psychiatry Suppl. 2002;43:s91–
behaviourally s97.
oriented service for relapse prevention in schizophrenia.
Acta Psychiatr Scand. 2010;121:340–350. 56. Tarrier N, Wittkowski A, Kinney C, McCarthy E, Morris J,
Humphreys L. Durability of the effects of cognitive-behav-
48. Feingold A. Effect sizes for growth-modeling analysis for
controlled clinical trials in the same metric as for classical ioural therapy in the treatment of chronic schizophrenia:
analysis. Psychol Methods. 2009;14:43–53. 12-month follow-up. Br J Psychiatry. 1999;174:500–504.
49. Woods SW. Chlorpromazine equivalent doses for the newer 57. Wykes T, Reeder C, Landau S, et al. Cognitive remediation
atypical antipsychotics. J Clin Psychiatry. 2003;64:663–667. therapy in schizophrenia: randomised controlled trial. Br J
50. Bechdolf A, Knost B, Kuntermann C, et al. A randomized Psychiatry. 2007;190:421–427.
comparison of group cognitive-behavioural therapy and 58. Reeder CH, Wykes T. Within-group differences in cognitive
group psychoeducation in patients with schizophrenia. Acta change and response to cognitive remediation therapy
Psychiatr Scand. 2004;110:21–28. (CRT). Schizophr Bull. 2007;33:574.
51. Valmaggia LR, Van der Gaag M, Tarrier N, Pijnenborg M, 59. Garety PA, Fowler DG, Freeman D, et al. Cognitive–behav-
Slooff CJ. Cognitive-behavioural therapy for refractory psy- ioural therapy and family intervention for relapse prevention
chotic symptoms of schizophrenia resistant to atypical anti- and symptom reduction in psychosis: randomised controlled
psychotic medication—randomised controlled trial. Br J trial. Br J Psychiatry. 2008;192:412–423.
Psychiatry. 2005;186:324–330.
60. McGrath J, Hayes RL. Cognitive rehabilitation for people with
52. Lindenmayer JP, McGurk SR, Mueser KT, et al. A random- schizophrenia and related conditions. Cochrane Database Syst
ized controlled trial of cognitive remediation among inpa-
Rev. 2000; CD000968. DOI: 10.1002/14651858.CD000968. (3).
tients with persistent mental illness. Psychiatr Serv.
2008;59:241–247. 61. Pfammatter M, Junghan UM, Brenner HD. Efficacy of
53. McGurk SR, Mueser KT, Derosa TJ, Wolfe R. Work, recov- psychological therapy in schizophrenia: conclusions from
ery, and comorbidity in schizophrenia: a randomized con- meta-analyses. Schizophr Bull. 2006;32:S64–S80.
trolled trial of cognitive remediation. Schizophr Bull. 62. Twamley EW, Jeste DV, Bellack AS. A review of cognitive
2009;35:319–335. training in schizophrenia. Schizophr Bull. 2003;29:359–382.

S110