Cognitive behavioural therapy for clozapine non-responders
Authors: Nina R Schooler
Journal: The Lancet Psychiatry (2018)

In The Lancet Psychiatry, Anthony Morrison and colleagues1Morrison AP Pyle M Gumley A et al.Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial.Lancet Psychiatry. 2018; (published online July 9.)http://dx.doi.org/10.1016/S2215-0366(18)30184-6Summary Full Text Full Text PDF Scopus (46) Google Scholar present the findings from their Focusing On Clozapine Unresponsive Symptoms (FOCUS) randomised clinical trial, in which they compared 9 months of cognitive behavioural therapy (CBT) for psychosis with treatment as usual for patients with schizophrenia who had not responded to treatment with clozapine. No between-group differences occurred for the primary outcome of Positive and Negative Syndrome Scale (PANSS) total score at 21 months (mean difference −0·89, 95% CI −3·32 to 1·55; p=0·48), Morrison and colleagues concluded that the results did not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia, but that a pragmatic trial might be indicated for some individuals.1Morrison AP Pyle M Gumley A et al.Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial.Lancet Psychiatry. 2018; (published online July 9.)http://dx.doi.org/10.1016/S2215-0366(18)30184-6Summary Full Text Full Text PDF Scopus (46) Google Scholar Reports of CBT being used to treat psychosis date back to the middle of the 20th century.2Beck AT Successful outpatient psychotherapy of a chronic schizophrenic with a delusion based on borrowed guilt.Psychiatry. 1952; 15: 305-312Crossref PubMed Google Scholar, 3Hole RW Rush AJ Beck AT A cognitive investigation of schizophrenic delusions.Psychiatry. 1979; 42: 312-319Crossref PubMed Google Scholar, 4Watts FN Powell GE Austin SV The modification of abnormal beliefs.Br J Med Psychol. 1973; 46: 359-363Crossref PubMed Scopus (109) Google Scholar Initial trials of this treatment focused primarily on medication-refractory patients with schizophrenia; thus, a review in 2000 addressed the use of CBT specifically in this patient population.5Garety PA Fowler D Kuipers E Cognitive-behavioral therapy for medication resistant schizophrenia.Schizophr Bull. 2000; 28: 73-86Crossref Scopus (138) Google Scholar Furthermore, the early studies targeted the symptoms (delusions and hallucinations), that define poor response to medication. CBT trials have since been extended to a broader range of patients earlier in their treatment course and the design of such trials has improved. CBT for psychosis is included in the UK National Institute for Health and Clinical Excellence guideline for both psychosis and schizophrenia in adults, and is recognised as an evidence-based practice by the Substance Abuse and Mental Health Services Administration in the USA.6National Institute of Health and Care ExcellenceNational Clinical Guideline number 178. Psychosis and schizophrenia in adults: treatment and management. National Institute of Health and Care Excellence, 2014Google Scholar The FOCUS trial represents an important addition to the understanding of CBT for psychosis, and incorporated several notable characteristics. First, the trial returned to the origins of CBT; ie, focusing on patients who were medication-resistant as defined by their resistance to clozapine, the only antipsychotic medication indicated for treatment of patients with medication-refractory schizophrenia. Treatment for these patients represents a major challenge for the field. Second, as a pragmatic trial done across a range of settings in the UK, it has enhanced generalisability of the results. Finally, the study was well designed and executed, with randomisation controlled to eliminate potential bias in allocation to treatment condition, CBT following a manual with clearly described training, and masking of the outcome assessments. Additionally, attrition between the end of treatment at 9 months and at 21-month follow-up was low. However, the choice of 21 months for the primary outcome measure, 12 months after the end of treatment, raises the question of how we should establish treatment efficacy in such studies. An important model for pharmacological treatments is the study of treatment discontinuation or relapse prevention. In such studies, individuals who have shown a response to a medication are randomly assigned to continue or discontinue that medication and are assessed for relapse or a return of the relevant symptoms. Findings from previous trials show consistently that those who continue medication fare better in terms of symptoms, as well as relapse or readmission to hospital, than those who discontinue.7Leucht S Tardy M Komossa K et al.Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis.Lancet. 2012; 379: 2063-2071Summary Full Text Full Text PDF PubMed Scopus (582) Google Scholar By contrast, for many psychosocial treatments persistence of an effect after discontinuation of treatment is often taken as the best evidence of efficacy.8White KS Payne LA Gorman JM et al.Does maintenance CBT contribute to long-term treatment response of panic disorder with or without agoraphobia? A randomized controlled clinical trial.J Consult Clin Psychol. 2013; 81: 547-557Crossref Scopus (29) Google Scholar This expectation regarding treatment effect represents the rationale for the decision to define the primary outcome in the FOCUS trial as the PANSS total symptom score at month 21—but is that the best measure for clozapine-resistant patients with schizophrenia? At the end of treatment at 9 months, there was a significant difference in PANSS total score for the CBT group versus the treatment-as-usual group (mean difference −2·40, −4·79 to −0·02; p=0·049). There were also significant differences between the groups for three of the five factors in the scale: positive symptoms, emotional distress and excitement. Thus, in clozapine non-responders, CBT seems to act similarly to pharmacological treatments and the results after treatment discontinuation suggests evidence of its effectiveness. Patients who do not respond to clozapine are among the most difficult to treat, and their symptoms cause them, their families, and clinicians great suffering. The conclusion that I have reached from the FOCUS study is that all patients who do not respond to clozapine should be offered CBT because it might provide relief from their distressing symptoms. When CBT ends, the significant effect might not persist; however, the challenge is to identify how to maintain or possibly increase its effects, while offering these patients the opportunity to experience the benefits that CBT can provide. I declare no competing interests. Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trialAt 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. Full-Text PDF Open Access