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Original Article |

Randomized Trial to Evaluate the Efficacy of Cognitive Therapy for Low-Functioning Patients With Schizophrenia FREE

Paul M. Grant, PhD; Gloria A. Huh, MSEd; Dimitri Perivoliotis, PhD; Neal M. Stolar, MD, PhD; Aaron T. Beck, MD
[+] Author Affiliations

Author Affiliations: Perelman School of Medicine, University of Pennsylvania, Philadelphia (Drs Grant, Stolar, and Beck and Ms Huh); and Veterans Affairs San Diego Healthcare System, San Diego, California (Dr Perivoliotis).


Arch Gen Psychiatry. 2012;69(2):121-127. doi:10.1001/archgenpsychiatry.2011.129.
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Published online

Context Low-functioning patients with chronic schizophrenia have high direct treatment costs and indirect costs incurred due to lost employment and productivity and have a low quality of life; antipsychotic medications and psychosocial interventions have shown limited efficacy to promote improved functional outcomes.

Objective To determine the efficacy of an 18-month recovery-oriented cognitive therapy program to improve psychosocial functioning and negative symptoms (avolition-apathy, anhedonia-asociality) in low-functioning patients with schizophrenia.

Design, Setting, and Participants A single-center, 18-month, randomized, single-blind, parallel group trial enrolled 60 low-functioning, neurocognitively impaired patients with schizophrenia (mean age, 38.4 years; 33.3% female; 65.0% African American).

Interventions Cognitive therapy plus standard treatment vs standard treatment alone.

Main Outcome Measures The primary outcome measure was the Global Assessment Scale score at 18 months after randomization. The secondary outcomes were scores on the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms at 18 months after randomization.

Results Patients treated with cognitive therapy showed a clinically significant mean improvement in global functioning from baseline to 18 months that was greater than the improvement seen with standard treatment (within-group Cohen d, 1.36 vs 0.06, respectively; adjusted mean [SE], 58.3 [3.30] vs 47.9 [3.60], respectively; P = .03; between-group d = 0.56). Patients receiving cognitive therapy as compared with those receiving standard treatment also showed a greater mean reduction in avolition-apathy (adjusted mean [SE], 1.66 [0.31] vs 2.81 [0.34], respectively; P = .01; between-group d = −0.66) and positive symptoms (hallucinations, delusions, disorganization) (adjusted mean [SE], 9.4 [3.3] vs 18.2 [3.8], respectively; P = .04; between-group d = −0.46) at 18 months. Age was controlled in the analyses, and there were no meaningful group differences in baseline antipsychotic medications (class or dosage) or in medication changes during the course of the trial.

Conclusion Cognitive therapy can be successful in promoting clinically meaningful improvements in functional outcome, motivation, and positive symptoms in low-functioning patients with significant cognitive impairment.

Trial Registration clinicaltrials.gov Identifier: NCT00350883

Figures in this Article

Between 2 and 3 million American adults currently have schizophrenia.1 The modal onset is in early adulthood,2 and roughly two-thirds of affected individuals experience a chronic or fluctuating course of illness.3 Annual overall direct treatment costs and indirect costs incurred due to lost employment and productivity approach $63 billion in the United States or an average of between $26 000 and $31 000 per patient,4 which is 5 times the per-patient cost of depression.5 Although antipsychotic medications have been demonstrated to reduce hallucinations and delusions, one-third to one-half of patients with schizophrenia continue to experience residual symptoms or have intolerable adverse effects.6,7 The disorganized (speech disturbance) and negative (affective flattening, alogia, apathy, anhedonia, and asociality) symptoms of schizophrenia are even less responsive to the medications than hallucinations and delusions.8 Importantly, the effect of medications on functional outcomes has been modest, even when medication regimens have been optimized.9

Starting in the 1950s, patients with schizophrenia have been moved from mental hospitals to the community.10 In Philadelphia, Pennsylvania, for example, patients enrolled in community mental health centers are offered supported housing and a wide range of therapeutic and vocational services; however, a large proportion continue to function at a low level. We sought to determine whether a novel version of cognitive therapy (CT) would lead to an increase in functioning and decreases in negative symptoms and positive symptoms (hallucinations, delusions, and disorganization) in this population. To determine the efficacy of this targeted CT derived from basic research and adapted to this population, we selected a sample of patients who were on the low end of the continuum of psychosocial functioning. This sample was also neurocognitively impaired (difficulties with information processing on tasks of memory, attention, and executive functioning) and experienced residual positive symptoms. Cognitive therapy (often labeled cognitive behavior therapy) has an extensive empirical basis in theory11 and has been successfully applied to a wide range of psychiatric problems.12 It was initially applied to schizophrenia by investigators in the United Kingdom,13 and results demonstrated success at reducing positive and negative symptoms.1417 Despite these encouraging findings, studies of CT have not focused on those patients with neurocognitive impairment and poor functioning. Similarly, studies of other psychosocial, behavioral, or neurocognitive remediation interventions have been limited by the following: a focus on acute rather than chronic psychosis, inclusion of a heterogeneous sample of patients, or a failure to find that treatment effects generalize adequately to psychosocial functioning.1822

In adapting CT for low-functioning patients with schizophrenia, we shifted the emphasis from the predominantly symptom-oriented approach that typifies the UK protocols to a person-oriented therapeutic approach by highlighting the patients' interests, assets, and strengths. The objective was to improve the level of functioning in the form of enhanced productivity, independence, and quantity and quality of social interactions. We developed the framework for our therapy from the finding that dysfunctional beliefs, in conjunction with neurocognitive impairment, impede functioning.2326 In addition, our therapy is largely influenced by the principles and spirit of the Recovery Movement.27,28 We focused our treatment methods on identifying and promoting concrete goals for improving quality of life and reintegration into society. In adapting our treatment protocol to this highly regressed group, we decided to extend the duration of treatment from the originally planned 12 months to 18 months. Further, we decided to focus on global functioning as a more appropriate measure of progress than simply the reduction of negative symptoms. Our protocol, in summary, differs from previous CT protocols for patients with schizophrenia in being explicitly recovery oriented, goal directed, and adapted for neurocognitive and skills impairments; it treats functional outcomes as primary rather than secondary targets of therapy and uses therapeutic conceptualizations based on new research on dysfunctional beliefs.

We conducted a randomized controlled trial to evaluate the efficacy of CT for neurocognitively impaired, poorly functioning patients with chronic schizophrenia.

The trial was conducted at a single center. The protocol and consent form were approved by 2 institutional review boards (the University of Pennsylvania and the City of Philadelphia). Each participant gave written informed consent before enrollment. Eligibility criteria included the following: diagnosis of DSM-IV schizophrenia or schizoaffective disorder; prominent negative symptoms (at least moderate severity on 2 Scale for the Assessment of Negative Symptoms29 global subscales, or marked severity on 1 subscale); aged 18 to 65 years; proficient in English; and able to give informed consent. Exclusion criteria included the following: neurologic disease or damage that would compromise cognitive functioning; and physical handicaps that would interfere with assessment procedures or therapy attendance. Diagnosis of schizophrenia or schizoaffective disorder was determined on a consensus best-estimate basis by research personnel (with PhD and MD degrees) using a structured interview conducted by an assessor trained to criterion (intraclass correlation > 0.80).30Figure 1 indicates the number of individuals who were screened and reasons for those who were not enrolled. Examples of reasons that patients gave for refusing the initial assessment included having an unstable living situation, having medical problems, or not wanting to receive one of the study conditions.

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Figure 1. Flowchart of the progress through the phases of the randomized trial for the 2 groups. CT indicates cognitive therapy; ST, standard treatment.

INTERVENTIONS

Participants were randomly assigned (1:1, stratified by sex because females with schizophrenia have a better course31 and may respond better to CT32) to the study intervention condition, CT plus standard treatment (ST), or to the control condition, ST alone, using an encrypted computer-generated randomization list. Personnel enrolling patients did not have access to this list. A single-blind design was used in which outcome assessors were not aware of assigned study condition. To maintain blinding, the assessment team was managed separately from the therapy team (in terms of personnel, physical location, and file access), and all participants were trained to not reveal their study condition prior to each follow-up assessment. (A total of 3 patients broke this rule at the 18-month assessment, 2 receiving CT and 1 receiving ST. Two of these patients were rated as unchanged on the primary outcome measure; 1 patient receiving CT was rated as improved modestly [6 points]. Even if this latter rating were inflated, it does not alter the pattern or significance of the results.) Furthermore, all available raters (6 of 7) were asked to guess the patient condition for each of their follow-up assessments (n = 103); assessors made 50 correct guesses and 53 incorrect guesses, a chance level of accuracy. Treatment assignment was known to therapists, patients, and, for legal reasons, the treating psychiatrist. Other members of each patient's nonstudy treatment teams (eg, group therapists, case managers) were not informed of treatment assignment.

Cognitive Therapy

Participants in the CT intervention were scheduled to receive up to 18 months of outpatient CT sessions. The sessions typically lasted 50 minutes and were scheduled on a weekly basis; however, based on the participant's needs and progress, the duration and frequency of sessions as well as duration of treatment were flexible. The central features of this psychotherapy were its goal-directed framework and personalized treatment planning. Early sessions focused on engaging the patient and strengthening the therapeutic relationship. Therapy aimed to stimulate patients' interest and motivation to focus respectively on achievable long-term goals (eg, independent housing, employment, relationships), intermediate goals, and short-term goals. Key impediments to reaching these goals are dysfunctional beliefs (eg,“taking even a small risk is foolish because the loss is likely to be a disaster” and“making new friends isn't worth the energy it takes”). The therapists helped patients to undercut their nihilistic beliefs and concomitantly increase their motivation for constructive activity by using a variety of cognitive and behavioral techniques, including activities during the session (eg, exercises, games, role-playing, community outings) and collaboratively devised action plans for practice outside the session. Other impediments to reaching the goals such as the presence of delusions, hallucinations, and disorganized thinking were also addressed by strategies outlined by Beck et al.33 Further, specific deficiencies such as deficits in attention, executive function, and social skills were targets for the therapy. Later sessions were devoted to consolidation of functional gains and relapse prevention. The treatment was tailored to the participant's level of functioning, such that special adaptations were made for problems due to poor engagement, neurocognitive impairment, thought disorder, and lack of insight. To accommodate neurocognitive impairments, for example, therapists made extensive use of visual aids, including whiteboards for reinforcing session material, laminated cards to help patients remember key take-home points, and colorful signs that patients posted at home to remind them of daily activities and other therapy assignments. The CT sessions followed a treatment manual and were administered by therapists at the doctoral level (PhD and MD). Sessions were videorecorded, and weekly supervision was provided by one of us (A.T.B.).

Standard Treatment

Participants in both study conditions received ST from clinicians in the community. At minimum, this consisted of antipsychotic pharmacotherapy. However, most participants were also actively engaged in services provided by local community mental health centers, including case management, supportive counseling, day treatment services, housing services, peer support, and vocational rehabilitation.

OUTCOMES

The primary objective of adding CT to ST was to aid the progress of patients with schizophrenia toward recovery by producing a clinically significant change in their functional outcome. The Global Assessment Scale (GAS)34 score was the primary outcome measure. The GAS is a single-item interviewer-scored instrument that assesses functioning level and symptoms during the previous month. The rating is made on a 100-point scale, with lower scores indicating poorer functioning. Endicott et al34 demonstrated test-retest reliability and predictive validity (rehospitalization rates) for the GAS in patients with schizophrenia. Secondary measures were the 4 global subscale scores of the Scale for the Assessment of Negative Symptoms (SANS)29 and the total score of the Scale for the Assessment of Positive Symptoms (SAPS).35 The reliability and validity of the SANS and SAPS have been demonstrated.36 A recent consensus statement has proposed the SANS and SAPS as standard measures of negative and positive symptoms.37

SAMPLE SIZE

On the basis of a meta-analysis of medical and behavioral outcomes showing that an effect size of d = 0.5 between conditions has an effect on quality of life,38 we designated d = 0.5 as the minimal clinically significant change that the trial would be powered to detect. With a sample size of 60, expected dropout rate of 20%, 2-sidedα = .05, and within-subject correlation of 0.5, we determined that the study would have 80% power to detect a true treatment difference in the rate of change of functioning of 0.5 SD.

PLANNED ANALYSES

Linear random-effects models (hierarchical regression models) were implemented with random intercepts and slopes. These models estimate main effects for change from baseline to each assessment at 6, 12, and 18 months, main effect for the treatment, and interactions between the visit and treatment indicator variables. For each of the primary (GAS) and secondary (SANS and SAPS) outcomes, separate intent-to-treat tests and estimates (with 95% CIs) of randomized group contrasts at 6, 12, and 18 months were obtained from the estimates of the respective time × treatment interactions.39 Potential confounding variables were evaluated by assessing whether baseline factors imbalanced between the treatment groups were related to outcome. Age was found to be a confounding variable (Table 1) and was controlled in all analyses. Although the study was designed to minimize lost observations, the random-effects or hierarchical regression approach is superior to last observation carried forward in minimizing bias and type I error and is inferentially equivalent to multiple imputation.40

Table Graphic Jump LocationTable 1. Baseline Demographic and Clinical Characteristics

Intent-to-treat analyses using hierarchical linear modeling were conducted on all outcome measures. The hierarchical linear modeling analysis is able to identify differences between conditions by the presence of a significant month × treatment interaction term. For example, a significant month × treatment interaction in favor of CT on the GAS score at 18 months would support the hypothesis that CT with ST is more efficacious than ST alone at improving functioning. Similar intent-to-treat analyses were run for negative and positive symptoms. Reported variances are standard deviations unless otherwise specified. Analyses were conducted using IBM SPSS version 19.0 statistical software (IBM Corp, Armonk, New York).

Between January 2007 and August 2009, 60 individuals were entered into the study, with 31 randomly assigned to CT with ST and 29 to ST alone. The mean (SD) age was 38.4 (11.6) years; 20 (33.3%) were female; and 39 (65.0%) were African American. The mean (SD) age at illness onset was 23.1 (8.5) years, and the mean (SD) duration of illness was 15.5 (12.18) years. The mean (SD) neurocognitive impairment in tasks of memory, attention, and executive functioning as measured by a validated computerized battery41 was a z score of−1.0 (1.2) relative to a healthy reference group, indicating considerable impairment in the sample. In terms of antipsychotic medication, 55 (91.7%) of the cohort was taking at least 1 atypical (second-generation) agent and 39 (65.0%) of the sample had a chlorpromazine equivalent dosage of 400 mg or greater, indicating a high dosage. There were no meaningful group differences in antipsychotic medications at baseline (Table 1 shows baseline sample characteristics).

As displayed in Figure 1, the 18-month trial was completed by 27 of the 31 participants (87.1%) in the CT group (1 died [hypertension] and 3 withdrew [refused treatment]) and by 24 of the 29 participants (82.8%) in the ST group (5 withdrew [2 moved away, 3 refused to continue participation]).

IMPLEMENTATION OF CT

The mean (SD) number of CT sessions for the 28 patients who engaged in treatment was 50.5 (18.9) (range, 16-81). The 8 therapists (with PhD and MD degrees), each having at least 2 years of experience with CT, treated an average of 3.5 patients (range, 1-7 patients).

TREATMENT WITH MEDICATIONS

There was no difference across the 2 conditions in the number of patients who changed medications or dosages.

OUTCOMES

The CT group improved on global functioning (GAS score) during the course of the trial (within-group Cohen d = 1.36), whereas the ST group improved very little (within-group d = 0.06) (Figure 2). In the intent-to-treat hierarchical linear model (Table 2), the interaction term for the condition × GAS score at 18 months was statistically significant (P = .03), indicating that the CT group had functioning superior to that of the ST group at 18 months (adjusted mean [SE], 58.3 [3.30] vs 47.9 [3.60], respectively; between-group d = 0.56).

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Figure 2. Global functioning. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; GAS, Global Assessment Scale; and ST, standard treatment. * P = .03 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

Table Graphic Jump LocationTable 2. Intent-to-Treat Hierarchical Linear Modeling Interaction Effects of Condition × 18 Months for Study Measures

On the 4 SANS negative symptom subscales (Figure 3), the CT group showed greater improvement than the ST group across the trial for avolition-apathy (at 18 months: within-group d,−2.16 vs−0.45, respectively; for interaction term of condition × 18 months, P = .01; adjusted mean [SE], 1.66 [0.31] vs 2.81 [0.34], respectively; between-group d = −0.66). There were no significant group differences for the other negative symptoms (affective flattening, alogia, anhedonia-asociality).

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Figure 3. Negative symptoms. The mean global scores for the avolition-apathy (A), anhedonia-asociality (B), affective flattening (C), and alogia (D) subscales of the Scale for the Assessment of Negative Symptoms (SANS) are shown. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; ST, standard treatment. * P = .01 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

In terms of positive symptoms (Figure 4), the CT group showed greater improvement than the ST group across the trial (at 18 months: within-group d,−0.90 vs 0.37, respectively; for interaction term of condition × 18 months, P = .04; adjusted mean [SE], 9.4 [3.3] vs 18.2 [3.8], respectively; between-group d = −0.46).

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Graphic Jump Location

Figure 4. Positive symptoms. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; SAPS, Scale for the Assessment of Positive Symptoms; and ST, standard treatment. * P = .04 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

We found that patients assigned to CT had better functioning, reduced avolition-apathy, and improved positive symptoms relative to patients who received ST only. Group differences were statistically significant and clinically meaningful. This is the first time, to our knowledge, that patients with chronic schizophrenia selected from the extreme end of the low-functioning continuum have shown statistically significant and clinically meaningful improvement in psychosocial functioning in response to a psychosocial intervention.

Taking the results of functional outcome, motivation, and positive symptoms together, we propose that the patients who received CT entered into a dynamic cycle of recovery. The treatment encourages the patients to set goals related to their everyday functioning, and they become motivated to engage in tasks (initially simple pleasurable, social, and constructive activities) that move them out of their withdrawn state. This increase in activity and motivation puts the patients more in touch with reality and reduces hallucinations, delusions, and disorganization. Reduced positive symptoms allow for further engagement in activity, leading to better functional outcomes and enhancement of motivation, which in turn facilitate a further amelioration of positive symptoms. Thus, we hypothesize that CT triggers the cycle of recovery by targeting self-defeating and dysfunctional beliefs that inhibit the patients' active engagement in constructive activity. Alternatively, it is possible that improvement in avolition-apathy was largely secondary to improvement in positive symptoms. These are questions that can be addressed by future research.

There are several limitations of this study. First, the measures of functioning and symptoms have been criticized.8,42 For instance, the GAS includes symptoms in the ratings and, as such, is not a pure measure of functional outcome. Use of the newly developed Schizophrenia Outcomes Functioning Interview43 and Clinical Assessment Interview for Negative Symptoms44 is warranted in future clinical trials of CT. More frequent assessment of symptoms and functioning would allow for better tracking of changes over time. Also, the therapy was delivered by doctoral-level therapists; generalization to masters-level community therapists who treat low-functioning patients remains to be demonstrated in future research. The CT condition involved more patient contact than the ST condition, raising the possibility that nonspecific patient contact factors are contributing to the observed group differences. Additionally, both therapists and patients were aware of the condition and participation in an experiment, introducing possible bias in the reported outcomes. Future studies can address nonspecific factors and bias due to single-blind design, as well as other factors, by comparing the CT protocol with active psychotherapy comparison conditions that feature treatments (eg, social skills) that have received empirical support for patients with schizophrenia. Finally, it remains for future studies with revised CT protocols to demonstrate efficacy relative to anhedonia, affective flattening, and alogia.

The major findings of this study—that CT improved functioning and motivation and reduced positive symptoms in low-functioning patients with schizophrenia—suggest that this treatment might have utility to help reduce public health costs for the most expensive per-patient psychiatric population while simultaneously improving patients' quality of life.

Correspondence: Paul M. Grant, PhD, Perelman School of Medicine, University of Pennsylvania, Room 2032, 3535 Market St, Philadelphia, PA 19104 (pgrant@mail.med.upenn.edu).

Submitted for Publication: May 17, 2011; final revision received July 13, 2011; accepted July 16, 2011.

Published Online: October 3, 2011. doi:10.1001/archgenpsychiatry.2011.129

Author Contributions: Dr Grant had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Drs Grant, Stolar, and Beck have received royalties from Guilford Press.

Funding/Support: This work was supported by a Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression (Dr Beck) and by grants from the Heinz Foundation and the Barbara and Henry Jordan Foundation.

Role of the Sponsors: The sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Additional Contributions: We express our gratitude to the patients who participated in this research and thereby made it possible. We also thank Arthur Evans Jr, PhD, and the City of Philadelphia Department of Behavioral Health; Roy Beck, MD, PhD; Thomas R. Ten Have, PhD, MPH; Robert A. Steer, EdD; Robert DeRubeis, PhD; LaRiena Ralph, BS, and Jan A. Richard, MS, Hospital of the University of Pennsylvania; and Gail Serruya, MD, Sunil Bhar, PhD, Sally Riggs, ClinPsyD, Luke Schultz, PhD, Jarrod Reisweber, PsyD, Nadine Chang, PhD, Amy Wenzel, PhD, Maureen Endres, MS, Mary Tabit, MS, Heath Hodges, MS, Kara Devers, MSEd, Sean Gallagher, MS, Jason Cha, MSEd, Ashley Chambers, MS, Michael Ovalle, MEd, and Letitia Travaglini, BS, University of Pennsylvania, for their assistance with this project.

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PubMed   |  Link to Article
Beck AT, Rector NA, Stolar NM, Grant PM. Schizophrenia: Cognitive Theory, Research and Therapy. New York, NY: Guilford Press; 2009
Endicott J, Spitzer RL, Fleiss JL, Cohen J. The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance.  Arch Gen Psychiatry. 1976;33(6):766-771
PubMed   |  Link to Article
Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City: University of Iowa; 1983
Andreasen NC. Methods for assessing positive and negative symptoms. In: Andreasen NC, ed. Schizophrenia: Positive and Negative Symptoms and Syndromes. Vol 24. Basel, Switzerland: Karger; 1990:73-88
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus.  Am J Psychiatry. 2005;162(3):441-449
PubMed   |  Link to Article
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation.  Med Care. 2003;41(5):582-592
PubMed
Bruce ML, Ten Have TR, Reynolds CF III, Katz II, Schulberg HC, Mulsant BH, Brown GK, McAvay GJ, Pearson JL, Alexopoulos GS. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial.  JAMA. 2004;291(9):1081-1091
PubMed   |  Link to Article
Schafer JL, Graham JW. Missing data: our view of the state of the art.  Psychol Methods. 2002;7(2):147-177
PubMed   |  Link to Article
Gur RC, Richard J, Hughett P, Calkins ME, Macy L, Bilker WB, Brensinger C, Gur RE. A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: standardization and initial construct validation.  J Neurosci Methods. 2010;187(2):254-262
PubMed   |  Link to Article
Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms.  Schizophr Bull. 2006;32(2):214-219
PubMed   |  Link to Article
Kleinman L, Lieberman J, Dube S, Mohs R, Zhao Y, Kinon B, Carpenter W, Harvey PD, Green MF, Keefe RSE, Frank L, Bowman L, Revicki DA. Development and psychometric performance of the schizophrenia objective functioning instrument: an interviewer administered measure of function.  Schizophr Res. 2009;107(2-3):275-285
PubMed   |  Link to Article
Blanchard JJ, Kring AM, Horan WP, Gur RC. Toward the next generation of negative symptom assessments: the collaboration to advance negative symptom assessment in schizophrenia.  Schizophr Bull. 2011;37(2):291-299
PubMed   |  Link to Article

Figures

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Graphic Jump Location

Figure 1. Flowchart of the progress through the phases of the randomized trial for the 2 groups. CT indicates cognitive therapy; ST, standard treatment.

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Graphic Jump Location

Figure 2. Global functioning. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; GAS, Global Assessment Scale; and ST, standard treatment. * P = .03 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

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Graphic Jump Location

Figure 3. Negative symptoms. The mean global scores for the avolition-apathy (A), anhedonia-asociality (B), affective flattening (C), and alogia (D) subscales of the Scale for the Assessment of Negative Symptoms (SANS) are shown. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; ST, standard treatment. * P = .01 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 4. Positive symptoms. The values at baseline are raw means; the values at 6, 12, and 18 months are adjusted means (SEs) from the intent-to-treat hierarchical linear models. CT indicates cognitive therapy; SAPS, Scale for the Assessment of Positive Symptoms; and ST, standard treatment. * P = .04 for the mean difference based on the hierarchical linear modeling interaction of treatment condition × assessment time.

Tables

Table Graphic Jump LocationTable 1. Baseline Demographic and Clinical Characteristics
Table Graphic Jump LocationTable 2. Intent-to-Treat Hierarchical Linear Modeling Interaction Effects of Condition × 18 Months for Study Measures

References

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McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology.  BMC Med. 2004;2(1):13-22
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Wu EQ, Birnbaum HG, Shi L, Ball DE, Kessler RC, Moulis M, Aggarwal J. The economic burden of schizophrenia in the United States in 2002.  J Clin Psychiatry. 2005;66(9):1122-1129
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Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, Corey-Lisle PK. The economic burden of depression in the United States: how did it change between 1990 and 2000?  J Clin Psychiatry. 2003;64(12):1465-1475
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Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RSE, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK.Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med. 2005;353(12):1209-1223
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Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials.  Schizophr Res. 1999;35(1):51-68
PubMed   |  Link to Article
Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia.  J Clin Psychiatry. 2010;71(9):1115-1124
PubMed   |  Link to Article
Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, Reimherr F, McGee MF, Keefe RSE, McEvoy JP, Hsiao JK, Lieberman JA.CATIE Investigators.  Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study.  Am J Psychiatry. 2007;164(3):428-436
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Warner R. Recovery From Schizophrenia: Psychiatry and Political Economy. 3rd ed. Hove, England: Brunner-Routledge; 2004
Clark DA, Beck AT. Scientific Foundations of Cognitive Theory and Therapy of Depression. New York, NY: John Wiley& Sons; 1999
Beck AT, Dozois DJ. Cognitive therapy: current status and future directions.  Annu Rev Med. 2011;62(1):397-409
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Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor.  Schizophr Bull. 2008;34(3):523-537
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Zimmermann G, Favrod J, Trieu VH, Pomini V. The effect of cognitive behavioral treatment on the positive symptoms of schizophrenia spectrum disorders: a meta-analysis.  Schizophr Res. 2005;77(1):1-9
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Sensky T, Turkington D, Kingdon D, Scott JL, Scott J, Siddle R, O’Carroll M, Barnes TRE. A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication.  Arch Gen Psychiatry. 2000;57(2):165-172
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Turkington D, Sensky T, Scott J, Barnes TRE, Nur U, Siddle R, Hammond K, Samarasekara N, Kingdon D. A randomized controlled trial of cognitive-behavior therapy for persistent symptoms in schizophrenia: a five-year follow-up.  Schizophr Res. 2008;98(1-3):1-7
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Hogarty GE. Personal Therapy of Schizophrenia and Related Disorders: A Guide to Individualized Treatment. New York, NY: Guilford Press; 2002
Kurtz MM, Mueser KT. A meta-analysis of controlled research on social skills training for schizophrenia.  J Consult Clin Psychol. 2008;76(3):491-504
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McGurk SR, Twamley EW, Sitzer DI, McHugo GJ, Mueser KT. A meta-analysis of cognitive remediation in schizophrenia.  Am J Psychiatry. 2007;164(12):1791-1802
PubMed   |  Link to Article
Granholm E, McQuaid JR, McClure FS, Auslander LA, Perivoliotis D, Pedrelli P, Patterson T, Jeste DV. A randomized, controlled trial of cognitive behavioral social skills training for middle-aged and older outpatients with chronic schizophrenia.  Am J Psychiatry. 2005;162(3):520-529
PubMed   |  Link to Article
Hogarty GE, Greenwald D, Ulrich RF, Kornblith SJ, DiBarry AL, Cooley S, Carter M, Flesher S. Three-year trials of personal therapy among schizophrenic patients living with or independent of family, II: effects on adjustment of patients.  Am J Psychiatry. 1997;154(11):1514-1524
PubMed
Grant PM, Beck AT. Defeatist beliefs as a mediator of cognitive impairment, negative symptoms, and functioning in schizophrenia.  Schizophr Bull. 2009;35(4):798-806
PubMed   |  Link to Article
Grant PM, Beck AT. Asocial beliefs as predictors of asocial behavior in schizophrenia.  Psychiatry Res. 2010;177(1-2):65-70
PubMed   |  Link to Article
Grant PM, Beck AT. Evaluation sensitivity as a moderator of communication disorder in schizophrenia.  Psychol Med. 2009;39(7):1211-1219
PubMed   |  Link to Article
Beck AT, Grant PM, Huh GA, Perivoliotis D, Chang NA. Dysfunctional attitudes and expectancies in deficit syndrome schizophrenia [published online May 27, 2011].  Schizophr Bull. 2011;
PubMed  |  Link to Article
Ralph RO, Corrigan PW. Recovery in Mental Illness: Broadening Our Understanding of Wellness. Washington, DC: American Psychological Association; 2005
Bellack AS. Scientific and consumer models of recovery in schizophrenia: concordance, contrasts, and implications.  Schizophr Bull. 2006;32(3):432-442
PubMed   |  Link to Article
Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City: University of Iowa; 1984
Nurnberger JIJ Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T.NIMH Genetics Initiative.  Diagnostic interview for genetic studies: rationale, unique features, and training.  Arch Gen Psychiatry. 1994;51(11):849-859
PubMed   |  Link to Article
Eaton WW, Chen C. Epidemiology. In: Lieberman JA, Stroup TS, Perkins DO, eds. Textbook of Schizophrenia. Washington, DC: American Psychiatric Publishing; 2006:17-37
Brabban A, Tai S, Turkington D. Predictors of outcome in brief cognitive behavior therapy for schizophrenia.  Schizophr Bull. 2009;35(5):859-864
PubMed   |  Link to Article
Beck AT, Rector NA, Stolar NM, Grant PM. Schizophrenia: Cognitive Theory, Research and Therapy. New York, NY: Guilford Press; 2009
Endicott J, Spitzer RL, Fleiss JL, Cohen J. The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance.  Arch Gen Psychiatry. 1976;33(6):766-771
PubMed   |  Link to Article
Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City: University of Iowa; 1983
Andreasen NC. Methods for assessing positive and negative symptoms. In: Andreasen NC, ed. Schizophrenia: Positive and Negative Symptoms and Syndromes. Vol 24. Basel, Switzerland: Karger; 1990:73-88
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus.  Am J Psychiatry. 2005;162(3):441-449
PubMed   |  Link to Article
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation.  Med Care. 2003;41(5):582-592
PubMed
Bruce ML, Ten Have TR, Reynolds CF III, Katz II, Schulberg HC, Mulsant BH, Brown GK, McAvay GJ, Pearson JL, Alexopoulos GS. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial.  JAMA. 2004;291(9):1081-1091
PubMed   |  Link to Article
Schafer JL, Graham JW. Missing data: our view of the state of the art.  Psychol Methods. 2002;7(2):147-177
PubMed   |  Link to Article
Gur RC, Richard J, Hughett P, Calkins ME, Macy L, Bilker WB, Brensinger C, Gur RE. A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: standardization and initial construct validation.  J Neurosci Methods. 2010;187(2):254-262
PubMed   |  Link to Article
Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms.  Schizophr Bull. 2006;32(2):214-219
PubMed   |  Link to Article
Kleinman L, Lieberman J, Dube S, Mohs R, Zhao Y, Kinon B, Carpenter W, Harvey PD, Green MF, Keefe RSE, Frank L, Bowman L, Revicki DA. Development and psychometric performance of the schizophrenia objective functioning instrument: an interviewer administered measure of function.  Schizophr Res. 2009;107(2-3):275-285
PubMed   |  Link to Article
Blanchard JJ, Kring AM, Horan WP, Gur RC. Toward the next generation of negative symptom assessments: the collaboration to advance negative symptom assessment in schizophrenia.  Schizophr Bull. 2011;37(2):291-299
PubMed   |  Link to Article

Correspondence

May 1, 2013
Munish Aggarwal, MD; Debasish Basu, MD, DNB
JAMA Psychiatry. 2013;70(5):543-544. doi:10.1001/jamapsychiatry.2013.284.
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Stimulating reward circuitries to diminish negative symptoms of schizophrenia
Posted on November 10, 2011
Laurent Lecardeur, Ph.D.
Centre Esquirol, CHU de CAEN, UMR 6232 CI-NAPS, GIP Cyceron, BP 5529, 14074 CAEN cedex, FRANCE
Conflict of Interest: None Declared
Grant et al.1 demonstrate that negative symptoms can be diminished using cognitive behavior therapies in low-functioning patients with schizophrenia. According to these authors, dysfunctional beliefs impede functioning and reintegration into society. Their aim is to discuss these beliefs so as to stimulate patients’ interest and motivation, identifying and promoting concrete objectives and achieving their goals with classical cognitive and behavioral techniques. Results demonstrate that patients assigned to cognitive therapy reduce avolition-apathy relative to patients who receive standard treatment. The authors highlight that treatment “encourages” and “motivates” patients “to engage in tasks that move them out of their withdrawn state”. However ‘‘reduced drive and motivation’’ is one of the most common symptoms even in the prodrome of first-episode psychosis, suggesting that amotivation is an intrinsic part of its pathology.2-4 Motivational deficits and apathy in schizophrenia might be induced hedonic deficits, a core negative symptom. However, several authors5,6 have suggested recently that patients with schizophrenia do not have an hedonic deficit in the strictest sense, but rather they can not anticipate the pleasure they could experience during activities.7 A therapeutic issue might be to stimulate consummatory pleasure7 (ie, pleasure derived from engaging in enjoyable activities) to engage patients in goal-directed activities. To this end, motivational interviewing could represent a useful add-on tool to cognitive therapy to diminish negative symptoms in schizophrenia. The challenge is to combine techniques of cognitive therapies and motivational interviewing. The first stage consists of cognitive and behavioural techniques as suggested by Grant et al.1 and targeting dysfunctional believes impeding in-vivo exposure to the pleasurable and rewarding activities. This point is essential since patients with schizophrenia reported as much pleasure in the moment as controls in their daily lives' activities.6 Through pleasure experiencing the objective is to stimulate dopaminergic reward circuitries and to induce biologically the patient’s need to re-experience this pleasure. In parallel the therapist has to use cognitive interviewing to develop the patient’s insight of pleasure experience and satisfaction through the identification of emotion, physical sensations and thoughts associated to the pleasure. Considering long term memory deficits displayed by patients with schizophrenia, this cognitive phase aims to encode a rich memory of the pleasurable experience, easier to retrieve by the patient during subsequent stage of the therapy. Motivational interviewing takes place in a second stage during which the patient is required to remember past pleasurable experiences and to compare them to other daily life activities. The more satisfying the activities, the more the individual will be motivated to re-experience these activities. Through the stimulation of reward circuitries during pleasurable activities, the patient will desire and need to achieve these goal-directed activities again. These techniques will place the patient in a virtuous circle of activities which can diminish degree of withdraw, passivity and inactivity. Considering amotivation in the early stage of psychosis,4 this therapeutic approach might be considered as promising tool against treatment resistant symptoms of psychosis.
Reference List
1. Grant PM, Huh GA, Perivoliotis D, Stolar NM, Beck AT. Randomized Trial to Evaluate the Efficacy of Cognitive Therapy for Low-Functioning Patients With Schizophrenia. Arch Gen Psychiatry 2011 October 3.
2. Faerden A, Finset A, Friis S, Agartz I, Barrett EA, Nesvag R, Andreassen OA, Marder SR, Melle I. Apathy in first episode psychosis patients: one year follow up. Schizophr Res 2010 January;116(1):20-6.
3. Kiang M, Christensen BK, Remington G, Kapur S. Apathy in schizophrenia: clinical correlates and association with functional outcome. Schizophr Res 2003 September 1;63(1-2):79-88.
4. Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996;22(2):353-70.
5. Foussias G, Remington G. Negative symptoms in schizophrenia: avolition and Occam's razor. Schizophr Bull 2010 March;36(2):359-69.
6. Gard DE, Kring AM, Gard MG, Horan WP, Green MF. Anhedonia in schizophrenia: distinctions between anticipatory and consummatory pleasure. Schizophr Res 2007 July;93(1-3):253-60.
7. Horan WP, Kring AM, Blanchard JJ. Anhedonia in schizophrenia: a review of assessment strategies. Schizophr Bull 2006 April;32(2):259-73.

Conflict of Interest: None declared
RCT in cognitive therapy--pragmatism of blinding & patients' preference
Posted on February 17, 2012
Devosri Sen, M.Sc, PG Dip in Rehabilitation Psychology
Central Institute of Psychiatry,
Conflict of Interest: None Declared
The article "Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia"1 and its methodology were read with great interest. Although a better methodological quality has here been tried, we would like to share some important pitfalls of the randomized design in blinded trials of cognitive therapy. The randomized controlled trial (RCT) has been seen as the optimal design for estimating treatment efficacy in medical experiments. In a blinded RCT, the placebo effect is equally distributed among treatment groups. In Grant et al's1 trial cognitive therapy gravitated to involve both the patient and the therapist being aware of the treatment that the patient was receiving. Thus, single blinding interferes with the power of the study. Consent for this study probably had been given prior to randomization (shown in figure 1). Thus, authors have not allowed for the patients' treatment preferences. Patients who receive their preferred treatment may experience greater improvements in the outcome because of added motivation to follow the treatment protocol than patients who do not receive their preferred treatment. Moreover, immediately following randomization three patients from each group refused to participate, which raises the possibility that participants could not understand the consent. In this instance, some alternatives to the RCT design could have been utilized. Firstly, randomized consent design (RCD) could have been used, whereby patients are randomized to treatment groups prior to informed consent and subsequently informed consent is only sought for those patients who are allocated to the experimental treatment.2 Here the sense of deprivation will be less in the standard treatment (ST) group, as they are unaware of the opportunity they had to receive a new treatment. Secondly, partially randomized preference trial (PRPT) could have been used, where patients without a treatment preference are randomized and patients with a treatment preference are allocated to the treatment of their choice. This design has recently been utilized in some studies with psychological interventions for depression. PRPTs have been recommended as they may improve the internal as well as external validity of clinical trials.3 However, this may be subject to the biases of an observational study and may not provide an unbiased measure of treatment effect. Thus in order to improve both internal and external validity further, Grant et al's1 RCT could have included a measure of preferences and detailed characteristics of those who refuse to take part in the study due to random allocation of treatment. This would enable preference effects to be measured at the analysis stage and enable authors to estimate the external validity of the trial. Thirdly, instrumental variable (IV) methods could have the advantage of adjustment for non- compliance and loss to follow up in their study. Instrumental variable is associated with treatment choice (e.g., proximity to the cognitive therapy clinic) but not with the outcome. Had the patients' preferences been taken care of in this study at least some of the eligible patients would have refused to participate in the study, especially those who live further away. Instrumental variable provides an estimate of treatment effect that is adjusted for some of the bias associated with the patient preference design.4
In the Grant et al1 study the experimental group was younger than the control group (p < 0.01) which might additionally contribute to intervention effect. Lastly, severity and domain of neurocognitive impairments might be a confounding factor, which if taken care of (i.e. by matching the groups) index study would have been methodologically more stringent and thus better powered.
Although we have discussed a few alternatives to RCT, which are especially legitimate for studies where participants express a preference for their treatment or blinding is less pragmatic, these designs are not free of biases. Nevertheless, they can enhance the external and internal validity of trials.
References:
1. Grant PM, Huh GA, Perivoliotis D, Stolar NM, Beck AT. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry.doi:10.1001/archgenpsychiatry.2011.129.
2. Zelen M. A new design for randomized clinical trials. N Engl J Med. 1979; 300: 1242-1245.
3. TenHave TR, Coyne J, Salzer M, Katz I. Research to improve the quality of care for depression: alternatives to the simple randomized clinical trial. Gen Hosp Psychiatry. 2003; 25: 115-123.
4. Greenland S. An introduction to instrumental variables for epidemiologists. Int J Epidemiol. 2000; 29: 722-729.
Authors:
Ms. Devosri Sen*M.Sc., P.G.Dip. [1], Dr. Partha Sarathi Biswas M.D., D.P.M. [2], Dr. (Prof.) V.K. Sinha M.D., D.P.M. [3]
Author Affiliation:
[1]. PhD Scholar, Department of Clinical Psychology, Central Institute of Psychiatry (CIP), Kanke, Ranchi, India;
[2]. Senior Resident, Department of Psychiatry, Ranchi Institute of Neuro-Psychiatry and Allied Sciences (RINPAS), Kanke, Ranchi, India;
[3]. Professor of Psychiatry, Central Institute of Psychiatry (CIP), Ranchi, India.
* Corresponding author
e-mail: devosri@gmail.com

Conflict of Interest: None declared
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