In Connecticut we have a wonderful Medicaid/T19/Behavioral Health program that allows home health nurses to monitor and/or administer medications for noncompliant mental health patients and home health aides to be in the home up to 14 hours a week to assist with medication reminders, ADLs, and IADLs.

I would be interested to know what impact our behavioral health nurses might have on an early-stage schizophrenia population versus our chronic noncompliant population. If we had our nurses in the home sooner, could we correct potentially problematic behavior before it became chronic?

View all comments by Wendy Camp

This paper is important because of its power and because this most basic question has never been satisfactorily answered. My concern is the very high dropout rate in both groups. Dropout across CBT of schizophrenia trials normally averages about 15 percent. CBT also usually attempts to work from a mini-formulation or macro-formulation which extends beyond the A-B-C. The CBT given here, however, does parallel the pragmatic technique-orientated CBT given in the Insight trial (Turkington et al., 2002). The problem here would appear to be the delivery of all four interventions in group format on the same day once per month. This is a massive burden on patients with cognitive deficits, negative symptoms, and treatment-resistant hallucinations and delusions. We must therefore be guarded about the conclusions. There is a signal, however, of the need for a psychosocial component in the management of every patient with schizophrenia. We are grateful to the authors for this publication.

References:

Turkington D, Kingdon D and Turner T. (2002) Effectiveness of a brief cognitive-behavioural therapy intervention in the treatment of schizophrenia. British Journal of Psychiatry 180, 523-527. Abstract

View all comments by Douglas Turkington

This study of a well-established, psychosocial treatment, which has been documented to be effective for depression, anxiety disorders, and positive symptoms of schizophrenia (Salkovskis, 1996; Kingdon and Turkington, 2004), presents credible evidence of efficacy for some, but not all, negative symptoms and possibly for social functioning in schizophrenia. The study has a number of strong methodological features; for example, protecting the “blind” for assessors, appropriate frequency and duration of treatment sessions necessary to achieve therapeutic outcomes in this population, controls for differences in types and doses of antipsychotic medication, a “standard treatment” comparison group which is consistent with the vast majority of community mental health, a sample that includes different racial and ethnic groups consistent with an inner-city population, and appropriate statistical analyses for measuring outcome. My comments address a number of concerns that may attenuate the clinical significance of the authors’ findings and interpretations.

Selection Criteria for...  Read more

Grant and colleagues are to be congratulated on their noteworthy trial. Anyone who has conducted clinical trials with seriously ill schizophrenia patients must be impressed by the ability of the research team to recruit a large cohort in an intensive treatment and keep them engaged over such a long period of time. The team also deserves credit for demonstrating that a psychosocial intervention can have a meaningful impact with this population. Added to the increasing literature on cognitive therapies with schizophrenia patients, and on recovery-based interventions, this report reinforces the argument that people with schizophrenia can and should be engaged as partners in the treatment process.

In a previous post, Bob Liberman identified a number of crucial limitations of this trial that raise questions about the findings and limit enthusiasm for the intervention. I concur with almost all of Bob's observations and analysis. The primary outcome variable (the GAS) has marked limitations and does not provide objective or detailed information about any changes in social or...  Read more

Grant and colleagues are to be congratulated on their noteworthy trial. Anyone who has conducted clinical trials with seriously ill schizophrenia patients must be impressed by the ability of the research team to recruit a large cohort in an intensive treatment and keep them engaged over such a long period of time. The team also deserves credit for demonstrating that a psychosocial intervention can have a meaningful impact with this population. Added to the increasing literature on cognitive therapies with schizophrenia patients, and on recovery-based interventions, this report reinforces the argument that people with schizophrenia can and should be engaged as partners in the treatment process.

In a previous post, Bob Liberman identified a number of crucial limitations of this trial that raise questions about the findings and limit enthusiasm for the intervention. I concur with almost all of Bob's observations and analysis. The primary outcome variable (the GAS) has marked limitations and does not provide objective or detailed information about any changes in social or occupational functioning in the community. Thus, the authors' conclusion that "cognitive therapy can be successful in promoting clinically meaningful improvements in functioning" is not supported by the data. We simply do not know much about community functioning beyond what the patients report, and the reports are especially suspect given that subjects receiving the cognitive therapy attended weekly sessions with a study therapist in which a primary focus of discussions was enhancing community activities and role functioning. A related concern pertains to the course of change noted on both the GAS and SANS ratings. The graphic representation of the data indicates that most, if not all, of the change manifested across measures occurred before the first (six-month) assessment. This raises questions about the operating mechanism of the CT intervention, as well as the value of the succeeding 12 months of treatment. As stated in the article, "Early sessions focused on engaging the patient and strengthening the therapeutic relationship." This implies that any changes induced during that early period may have resulted from non-specific effects rather than any specific cognitive therapy activities. Given that (almost) no community program could afford to administer a weekly individual treatment for 18 months, it should be underscored that at best, the data do not support anything beyond six months of treatment.

Another important issue noted by Liberman was the multifaceted composition of the CT intervention. It included elements of cognitive therapy, skills training, behavior therapy, motivational enhancement, and cognitive remediation, among others. In fact, it is difficult to justify calling the intervention "cognitive therapy" when so little of it entails cognitive therapy per se. While most of the elements have face validity and independent empirical support, the resulting combination has two significant limitations. First, it is impossible to determine the active components of the treatment. Second, it would be virtually impossible to replicate or disseminate the intervention. This latter point is of particular concern, as the trial has been reported in the media (e.g., The New York Times) as demonstrating that cognitive therapy is effective for schizophrenia patients with negative symptoms. To the contrary, this trial does not demonstrate that CT is effective for reducing negative symptoms, or that CT is a cognitive therapy.

In sum, this is an important trial that should and will have an important heuristic role for the field. It is a trial that should have been done and probably could not have been done by any other research group. While acknowledging and applauding its strengths and value for the field, it is important to consider its limitations and be cautious about what conclusions can be drawn from the results.

We thank Professors Liberman and Bellack for their thoughtful critiques of our work and welcome the opportunity to answer their questions and concerns, and thereby clarify our study beyond the space limitations of the original paper.

Liberman and Bellack express several concerns regarding the number and types of techniques employed in therapy, as well as the length of therapy. Liberman states that our therapy is “confounded” with other treatment approaches because the intervention contains many treatment techniques (e.g., skills training, cognitive remediation, motivational enhancement) that overlap with other psychosocial treatments for schizophrenia; Bellack indicates that he does not believe our treatment should properly be called “cognitive therapy” because “so little of it entails cognitive therapy per se.” We appreciate that they have raised this issue because it affords us an opportunity to explain in greater detail why we use the term cognitive therapy and what we mean by it.

Our formulation of cognitive therapy is based on the cognitive model of schizophrenia...  Read more

We thank Professors Liberman and Bellack for their thoughtful critiques of our work and welcome the opportunity to answer their questions and concerns, and thereby clarify our study beyond the space limitations of the original paper.

Liberman and Bellack express several concerns regarding the number and types of techniques employed in therapy, as well as the length of therapy. Liberman states that our therapy is “confounded” with other treatment approaches because the intervention contains many treatment techniques (e.g., skills training, cognitive remediation, motivational enhancement) that overlap with other psychosocial treatments for schizophrenia; Bellack indicates that he does not believe our treatment should properly be called “cognitive therapy” because “so little of it entails cognitive therapy per se.” We appreciate that they have raised this issue because it affords us an opportunity to explain in greater detail why we use the term cognitive therapy and what we mean by it.

Our formulation of cognitive therapy is based on the cognitive model of schizophrenia (Beck et al., 2009) rather than specific techniques. Basically, we view the low-functioning problems in these patients as due to the interaction of neurocognitive deficits and negative attitudes about performance and social relations. Our basic research has shown both in cross-sectional (Grant and Beck, 2009; Grant and Beck, 2009) and longitudinal (Grant and Beck, 2010) studies that these low-functioning patients have very powerful negative attitudes about the possibility of achieving any goals (e.g., “there is no point in trying because I will only fail”), as well as negative attitudes about the desirability of social contact. In non-technical terms, these patients have given up and have walled themselves off from usual activities of everyday life because of their expectations that they are only going to fail if they try something. While there evidently is an upper limit on how much they can achieve due to their neurocognitive deficits, they do have considerable latent capacity that they are not utilizing. Since the negative attitudes seem to account for their loss of motivation, we use a variety of methods to ameliorate them. Since we frame the problems in cognitive terms, and our understanding of each case is based on a cognitive model, we utilize the term cognitive therapy. We would, therefore, expect that any change would be mediated by cognitive variables. To produce this change, we formulate each case in terms of the individual’s goals and identify the various obstacles to reaching these goals. We select specific techniques ranging from skills training, problem solving, explicit cognitive restructuring, etc., to overcome these obstacles. If the patient is blocked by social inhibition, we use assertiveness training; if the problem is fear of failing, we use cognitive restructuring. According to our thesis, each specific successful experience tends to undercut the negative attitudes that sap the patient’s motivation. Support for our formulation is based on an experimental study which showed that success experiences not only modify negative attitudes, but increase motivation and performance (Perivoliotis et al., 2011). Once the patients start to modify their attitudes, they become more engaged in real life and begin to take advantage of various rehabilitative services that are offered. The question of when and how to apply these strategies is described in the volume by Perivoliotis, Grant, and Beck (Perivoliotis et al., in press).

The multifaceted nature of our CT intervention prompts both Bellack and Liberman to wonder about the mechanism of change. In response to Bellack’s concern that it would be impossible to determine the “active ingredients” of the treatment, we propose that the beliefs targeted by the formulation-driven interventions are producing change. Mediation analysis (beliefs as mediators) would allow us to test this hypothesis. Liberman, in a similar vein, proposes several alternative explanations for our results: behavioral methods, social anxiety, positive symptoms, and medication adherence. He also proposes that, since we did not observe changes in alogia, we did not really affect social functioning. In regard of this last point, we think it is notable that the mean alogia ratings were in the questionable to mild range at baseline and remained in this range throughout the course of the trial. This finding suggests that if improvements were made, it is unlikely that they would be clinically meaningful due to a floor effect.

Additionally, it does not seem likely that the global improvement in the patients’ functioning was due to compliance with medication, since previous research has shown minimal impact from medication (Swartz et al., 2007). However, if medication compliance was improved, this would indicate a positive result from our multifaceted intervention. A similar argument extends to positive symptoms and social anxiety. Finally, while it is possible that behavioral methods could be the mechanisms of change in our study, it is also possible that cognitive change is produced by social skills training and cognitive remediation. We think that exploring beliefs in psychosocial treatments for schizophrenia is a rich area to pursue.

Bellack makes three final points regarding the CT treatment: he questions whether it would be possible to “replicate or disseminate the intervention”; he proposes that our data do not support providing more than six months of CT; and he suggests that “all of the changes induced during that early period may have resulted from non-specific effects rather than any specific cognitive therapy activities.” In regard to dissemination, we have already successfully trained masters-level community therapists in the manualized intervention, and have applied for funding to conduct a systematic study. As to the length of treatment, 50 sessions was the average for the entire group in the study: some participants completed therapy in fewer sessions and some required more. Thus, consistent with an individualized recovery orientation, we argue that some patients can benefit from shorter course of therapy whilst others will require more sessions. This is a matter for future study. And, in regard to non-specific factors, the best way to test this alternative hypothesis is to conduct a new study that compares CT to a supportive therapy control group.

Turning to the methods of the study, both authors are concerned about the measurement of functioning in our study. Liberman states that we did not use a well-established and psychometrically sound assessment instrument measuring social functioning for inclusion, while Bellack and Liberman both criticize our outcome measure as inadequate. We did not specifically describe social functioning as a key outcome, but rather global functioning. The Global Assessment Scale (GAS) was a conventional measure of global functioning at the time we initiated our study. Since that time, new measures have been developed, such as the Schizophrenia Objective Functioning Instrument (SOFI; Kleinman et al., 2009), and research by Phil Harvey’s group (Harvey et al., 2011; Leifker et al., 2011) has indicated that the preferred measure of functioning is the Specific Levels of Functioning scale (SLOF; Schneider and Struenging, 1983). In our next study, we plan to use the SLOF as the primary outcome measure.

Liberman proposes that our sample may not have been composed of patients with primary negative symptoms. In other words, the patients in the study had negative symptoms that were secondary to positive symptoms, with the observed improvement in negative symptoms being produced by improvement in positive symptoms. We did not formally assess primary versus secondary negative symptoms in the clinical trial. However, clinically, we observed that defeatist beliefs occurred independently of the presence of positive symptoms. And, as the beliefs were modified by the CT treatment, patients improved.

Finally, Bellack suggests our data do not support the conclusion that “cognitive therapy can be successful in promoting clinically meaningful improvements in functioning.” We disagree with his inference. We believe the intervention, by whatever name, produced successful results, as was evident in the collateral reports factored into the ratings of functioning.

The authors wish to acknowledge the contributions of Drs. Jessica Murakmi-Brundage and Yael Perry in developing this response.

References:

1. Beck AT, Rector NA, Stolar NM, Grant PM. Schizophrenia: Cognitive Theory, Research and Therapy. NY: Guilford Press; 2009.

2. Grant PM, Beck AT. Defeatist beliefs as a mediator of cognitive impairment, negative symptoms, and functioning in schizophrenia. Schizophr Bull. Jul 2009;35(4):798-806. Abstract

3. Grant PM, Beck AT. Evaluation sensitivity as a moderator of communication disorder in schizophrenia. Psychol Med. Jul 2009;39(7):1211-1219. Abstract

4. Grant PM, Beck AT. Asocial beliefs as predictors of asocial behavior in schizophrenia. Psychiatry Res. 2010;177(1-2):65-70. Abstract

5. Perivoliotis D, Grant PM, Beck AT. The impact of success in low-functioning schizophrenia: an analogue study. International Conference on Schizophrenia Research. Colorado Springs, CO. April 02, 2011.

6. Perivoliotis D, Grant PM, Beck AT. Cognitive behavior therapy for schizophrenia: a comprehensive treatment manual. New York: Guilford; in press.

7. Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, Reimherr F, McGee MF, Keefe RSE, McEvoy JP, Hsiao JK, Lieberman JA, Investigators ftC. 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. Abstract

8. 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. Abstract

9. Harvey PD, Raykov T, Twamley EW, Vella L, Heaton PK, Patterson TL. Validating the measurement of real-world functional outcomes: phase I results of the VALERO study. Am J Psychiatry. 2011;168:1195-1201. Abstract

10. Leifker FR, Patterson TL, Heaton PK, Harvey PD. Validating measures of real-world outcome: the results of the VALERO expert survey and RAND panel. Schizophr Bull. 2011;37:334-343. Abstract

11. Schneider LC, Struenging EL. SLOF: a behavioral rating scale for assessing the mentally ill. Soc Work Res Abstr. 1983;19:9-21.

The notion that cognitive remediation is effective in producing cognitive and functional gains in established schizophrenia (Wykes et al., 2011), and produces other gains such as changes identified in brain imaging (e.g., Wykes et al., 2002) is unsurprising. But the paper on remediation in adolescent rats by Lee and colleagues provides results that the authors do consider surprising, and could lead to further extensions of cognitive remediation to those who are "at risk" for disorders such as schizophrenia. This is because of the procognitive effects of providing training in youthful rats.

Procognitive effects of experience-based training are not, however, surprising. The authors quote research showing that there are functional changes with training—the one that springs to my mind is London taxi drivers whose hippocampi are larger following their "training" for The Knowledge—an all-roads-in-London test. So why are the authors surprised? Perhaps it is because the results...  Read more

The notion that cognitive remediation is effective in producing cognitive and functional gains in established schizophrenia (Wykes et al., 2011), and produces other gains such as changes identified in brain imaging (e.g., Wykes et al., 2002) is unsurprising. But the paper on remediation in adolescent rats by Lee and colleagues provides results that the authors do consider surprising, and could lead to further extensions of cognitive remediation to those who are "at risk" for disorders such as schizophrenia. This is because of the procognitive effects of providing training in youthful rats.

Procognitive effects of experience-based training are not, however, surprising. The authors quote research showing that there are functional changes with training—the one that springs to my mind is London taxi drivers whose hippocampi are larger following their "training" for The Knowledge—an all-roads-in-London test. So why are the authors surprised? Perhaps it is because the results may have further implications for treatment and prevention, but only if followed up in those who are “at risk,” a notion that has produced much heat and not much light in the annals of SRF. We have been optimistic about the possibility of change in prodromal patients using cognitive behavioral therapy, but that hope has not yet been justified in the current research. It may be that this form of experience-based learning is of greater help in the prodromal group than the traditional cognitive behavioral therapies. It may also be that we need to begin our interventions in school by identifying those who are cognitively at risk for many different future problems, not just schizophrenia.

The results also suggest that even when there is a known lesion, it is possible to normalize behavior as well as produce some correlated neuronal change. This is exciting, as it opens up the possibility of finding cures, if not for the whole disorder at least for some of the problems or symptoms of schizophrenia. All this can be produced by a non-pharmacological intervention. This is something that will surely excite the providers of healthcare, as the cost-benefit would be very high if the future health costs for these patients were reduced through such means.

References:

Wykes T, Brammer M, Mellers J, Bray P, Reeder C, Williams C, Corner J. Effects on the brain of a psychological treatment: cognitive remediation therapy: functional magnetic resonance imaging in schizophrenia. Br J Psychiatry. 2002 Aug;181:144-52. Abstract

Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry . 2011 May ; 168(5):472-85. Abstract

In their new Neuron article, Lee and colleagues from Andre Fenton’s group at NYU report that spatial cognitive control deficits in a rat model of schizophrenia can be prevented through a ratish analogue of cognitive remediation therapy during adolescence. The importance of early intervention has been one of the hottest debates in applied schizophrenia research; the current findings suggest a basic mechanism in support of such efforts.

What is remarkable about the Fenton study is how small a training “dosage” was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the rats’ capacity to use spatial cognitive control eight to nine weeks after birth.

Rats were sacrificed at the end of the experiment, allowing the researchers to examine the extent to which the initial lesion had affected brain development. The initial lesions dramatically altered hippocampal development. Despite this, lesioned rats who received training did not show any observable difference in brain morphology in adulthood...  Read more

In their new Neuron article, Lee and colleagues from Andre Fenton’s group at NYU report that spatial cognitive control deficits in a rat model of schizophrenia can be prevented through a ratish analogue of cognitive remediation therapy during adolescence. The importance of early intervention has been one of the hottest debates in applied schizophrenia research; the current findings suggest a basic mechanism in support of such efforts.

What is remarkable about the Fenton study is how small a training “dosage” was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the rats’ capacity to use spatial cognitive control eight to nine weeks after birth.

Rats were sacrificed at the end of the experiment, allowing the researchers to examine the extent to which the initial lesion had affected brain development. The initial lesions dramatically altered hippocampal development. Despite this, lesioned rats who received training did not show any observable difference in brain morphology in adulthood compared to lesioned rats who did not receive training. That is to say, the integrity of the hippocampus measured grossly did not predetermine that rats would perform poorly on the spatial cognitive control task—if they received training. However, subsequent analysis demonstrated that phase synchronization between the hippocampus and prefrontal cortex (which rats possess, albeit not in extremis) was compromised in the lesioned rats who did not receive training, but was recovered in those that did receive training.

Thus, the data suggest that fundamentally important circuitry can be guided through training that is relevant for later cognitive functioning.

What is absent is evidence for the specialness of adolescent intervention. This seems to be assumed from previous work rather than the result of comparisons of implementing the intervention at different ages.

It’s also interesting to note that hippocampal lesion models are generally evaluated using memory-related tasks. Fenton’s task presents something of a hybrid. The spatial cognitive control paradigm used is appropriately adapted to the species in question, but in the abstract it has features similar to that of the Stroop task. In Fenton’s active place avoidance task, there is a dominant channel for responding on which the rat is over-trained, like the Stroop task's word reading component on which most people reading this text have been over-training. There is also a subordinate channel for responding, with which the rat is familiarized, something like color naming on the Stroop task. However, a key aspect of the manipulation is the inability to learn a new zone to avoid, which may be more akin to perseveration than to Stroop performance. Rotation of shock zone to a new location is described as task transference, but since the original learning was a source of interference (and needed to be inhibited) in the subsequent task, I’m not sure I agree with this description.

This work will be warmly received by a large number of advocates who are pushing for interventions earlier in the risk period. One advantage the authors had compared to those in the clinical schizophrenia field is that they knew which of their rats were strongly exposed and were therefore at the highest risk. While our screening tools have been honed over the past decade, they still have a high false-positive rate. One can take some solace, though, that cognitive remediation is unlikely to have extensive negative side effects. Except, perhaps, boredom.

I am always a little skeptical of animal models of psychosis or schizophrenia, which are pretty high-order disturbances and seem very specific to humans. If this model has some validity, the preventive therapy in humans would be more akin to cognitive remediation therapy rather than cognitive therapy per se, which has more CBT links or connotations.

View all comments by Patrick McGorry

Lee et al. report exciting new data in support of the neurodevelopmental hypothesis of schizophrenia and the plausibility of the early intervention that might prevent the emergence of schizophrenia symptoms. Lee and colleagues used a neonatal ventral hippocampal lesion in rats as a model of schizophrenia.

First, using the active place avoidance task with carefully designed control tasks, they showed that the animals with neonatal lesions are cognitively impaired as adults, consistent with the results of the previous studies (see Tseng et al., 2009, for review). Next, they examined whether training of the lesioned animals in adolescence would prevent the emergence of these abnormalities. They exposed the animals to a series of cognitive tests and found that, indeed, the neonatally lesioned rats that acquired additional training as adolescents showed improved cognition in adulthood. Moreover, specific measures of neural function were also improved. The authors recorded local field potentials in the hippocampi and found that the...  Read more

Lee et al. report exciting new data in support of the neurodevelopmental hypothesis of schizophrenia and the plausibility of the early intervention that might prevent the emergence of schizophrenia symptoms. Lee and colleagues used a neonatal ventral hippocampal lesion in rats as a model of schizophrenia.

First, using the active place avoidance task with carefully designed control tasks, they showed that the animals with neonatal lesions are cognitively impaired as adults, consistent with the results of the previous studies (see Tseng et al., 2009, for review). Next, they examined whether training of the lesioned animals in adolescence would prevent the emergence of these abnormalities. They exposed the animals to a series of cognitive tests and found that, indeed, the neonatally lesioned rats that acquired additional training as adolescents showed improved cognition in adulthood. Moreover, specific measures of neural function were also improved. The authors recorded local field potentials in the hippocampi and found that the neonatally lesioned animals showed deficits in interhippocampal synchrony, the findings similar to the changes reported in patients with schizophrenia. Adolescent cognitive training normalized interhippocampal synchrony and improved performance on the cognitive tasks in the neonatally hippocampally lesioned rats. Finally, to gain more insight into the mechanisms of these changes, the authors measured cortical thickness and parvalbumin protein content, but these parameters were not informative about the benefits of cognitive training in this animal model of schizophrenia.

The results of this study support the notion that schizophrenia is a neurodevelopmental disorder characterized by discoordinated neural networks, and provide critical evidence for the benefits of early behavioral intervention. Although we still do not fully understand the pathophysiological mechanisms underlying schizophrenia, or the mechanisms responsible for the improvements due to cognitive training, this work certainly offers a potential new therapeutic tool in the form of preemptive cognitive therapy.

References:

Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res . 2009 Dec 7 ; 204(2):295-305. Abstract