Therapy-Resistant Schizophrenia

H. Elkis, H. Y. Meltzer, W. P. Kaschka, W. F. Gattaz

• Publisher: S. Karger
• Year: 2010
• Print ISBN: 9783805595117
• eBook ISBN: 9783805595124
• Topic: Medicine
• Subtopic: Neurology

The psychotic symptoms of up to 30% of schizophrenic patients do not respond adequately to treatment with antipsychotic drugs, other than clozapine. These refractory patients are generally among the most disabled of all people with schizophrenia and require special assessment and treatment. This volume presents the latest research and recommendations on the definition, causes and therapy of treatment-resistant schizophrenia (TRS). Methods for identification and optimal management of TRS are reviewed. Clozapine and other atypical antipsychotic drugs which are the primary treatment for TRS, as well as non-pharmacologic treatments such as transcranial magnetic stimulation, cognitive behavior therapy and ECT are discussed in depth. Potential causative factors and identifying features such as genetic factors, poor premorbid functioning, longer duration of untreated psychosis, and biological measures such as structural and functional brain abnormalities are also reviewed in depth in the present volume.

Concepts and Assessment

Elkis H, Meltzer HY (eds): Therapy-Resistant Schizophrenia.
Adv Biol Psychiatry. Basel, Karger, 2010, vol 26, pp 9–32

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Assessment of Therapy-Resistant Schizophrenia

J.P. Lindenmayer^a · Anzalee Khan^b

^aNew York University School of Medicine and ^bFordham University, New York, N.Y., USA

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Abstract

It is generally accepted that between 10 and 60% of patients with schizophrenia respond poorly or only partially to antipsychotic treatment, even if they take their antipsychotic medication reliably. Early identification of patients with treatment-resistant schizophrenia (TRS) is crucial as specific treatments for these patients can then be initiated earlier and progression towards clinical deterioration can be attenuated. Assessing patients with suspected TRS requires a comprehensive and multi-systems approach, ranging from the longitudinal course assessment, to the symptom/functional assessments, to the biological assessments. The aim of this chapter is to review the definition and diagnosis of TRS, some of its clinical correlates and the recommended assessments of patients with TRS. Definitions of TRS are reviewed and a more comprehensive definition is presented, which uses a multidimensional concept of TRS consisting of: (1) distinct domains of psychopathology, which are treatment resistant and (2) the view that treatment response often is only partial. The distinct domains of psychopathology include persistent positive symptoms, persistent negative symptoms, persistent depressive-anxiety symptoms (including suicidality), persistent excitement symptoms (including aggressive/violent behavior) and persistent cognitive symptoms. These symptom domains should replace the traditional positive-negative distinction of schizophrenic phenomenology. We further review steps to aid in assessing TRS, which include the assessment of the specific domain that is showing an inadequate response, the determination of how many antipsychotic trials and what type of trials are documented, and whether certain medications or classes of medications were given before a patient is determined to be resistant to treatment. TRS has to be considered if there is a failed response after optimizing the dose of at least 2 trials of antipsychotic medication and after checking serum levels, and after ruling out adverse effects of psychiatric and other medications that may mimic worsening of symptoms. An assessment of comorbid conditions - such as substance use disorders, depression, and obsessive-compulsive disorder, which may contribute to TRS - is provided. Once TRS has been established together with some possible contributing etiological factors, a comprehensive treatment plan can be developed, which will take into account the identified etiological factors.

Copyright © 2010 S. Karger AG, Basel

Treatment-resistant schizophrenia (TRS) can have a devastating effect on individuals and families. It also represents a significant public health problem. Although estimates vary widely, it is generally accepted that between 10 and 60% of patients with schizophrenia respond poorly or only partially to antipsychotic treatment [1-4]. Moreover, 20-30% of patients will still relapse during the first year of maintenance treatment with conventional antipsychotics, even if they take their medication reliably [3, 5]. It is also known that between 40 and 60% of patients with schizophrenia attempt suicide [6], and some of the worst-case outcomes are more likely to occur in treatment-resistant patients [6]. The public health and economic implications are significant. A substantial number of inpatient psychiatric beds are occupied by treatment-resistant patients. As state hospitals in the United States continue to diminish in both number and size, these patients are now increasingly found in short-term general hospital units, the prison system and homeless shelters, where treatment resources are inadequate. Patients with TRS typically have longer lengths of stay when they are hospitalized, and when in the community, their level of functioning is generally very poor. As a result, they use disproportionate amounts and levels of community psychiatric resources, such as psychiatric emergency rooms, repeated short-term inpatient stays, intensive case management and day hospitals. Finally, the high degree of disability and reduced rate of return to gainful employment result in a high degree of dependence on government-sponsored benefits producing a substantial burden on the economy. The aim of this chapter is to review the diagnosis of TRS, some of its clinical correlates and the recommended assessments of patients with TRS.

History and Development of TRS

Schizophrenia has historically been perceived as a deteriorating disease and the term ‘dementia praecox’ was created by Kraeplin [7] to highlight this early deterioration. However, more recent research has questioned the existence of a progressive neurodegenerative process [8-11]. The argument centers on whether schizophrenia patients reach the first florid episodes after initial abnormal neurodevelopment and then remain in a reasonably stable clinical state or whether there is a descending evolution of the illness after the initial episode that yields clinical deterioration and/or treatment resistance. Supporting a kraepelinian [7] view of schizophrenia is the finding that patients with TRS show an increment in lateral cerebral ventricles’ size that continues developing, especially in the left hemisphere, indicating a neurodegenerative process [12]. Supporting the latter view, evidence of neurodevelopmental factors have been associated with poor treatment outcomes (e.g. low premorbid functioning, increased evidence of obstetrical complications and early presence of a deficit state [13-16]).

It is likely that both these positions are represented in the course of schizophrenia to various degrees. This is also reflected in the presentation of TRS, which may be observed for some patients at the time of onset of florid illness; treatment resistance may be as high as 15% even in non-chronic first-episode patients [17]. More commonly, TRS develops over the course of the patient's illness [18]. The presence of TRS is most likely also affected by treatment interventions or the lack thereof. On the one hand, the treatment response of some schizophrenia patients has improved with the ongoing development of pharmacological agents and increased efficacy of psychosocial and neurocognitive treatments [19]. On the other hand, there is some evidence that the duration of untreated psychosis early in the onset of overt illness is associated with poorer treatment response [20-22]. However, there is a fair consensus that some patients with schizophrenia show progressive treatment non-response over the course of their illness either because of its progression or because they become less responsive to treatment [7, 23-26].

Combining neurodevelopmental and neurodegenerative aspects of the evolution of schizophrenia, TRS has been proposed to develop according to 3 stages [27, 28]: (1) cortical pathology and deficient neuromodulatory capacity resulting from genetic/ epigenetic etiologic factors occurring during childhood; (2) neurochemical sensitization leading to dopamine release and development of psychotic episodes occurring during adolescence; (3) neurotoxicity with consequent development of structural neuronal changes in adulthood. Therefore, it is conceivable that brain abnormalities may underlie the development of resistance to treatment in schizophrenia.

Despite significant advances in the understanding of the neurophysiology and pathogenesis of schizophrenia and the development of newer antipsychotics, TRS remains a difficult problem and needs to be addressed in most patients with schizophrenia at some time in their illness evolution. In order to better address TRS and to develop specific treatment approaches, it is important to examine what defines TRS.

Definitions of TRS

The concept of non-response to treatment has been used in different ways. Terms such as suboptimal, partial response and treatment refractory have all been used to refer to this concept. In earlier discussions of the TRS concept, 2 forms have been differentiated: (1) Kraepelinian schizophrenia, which denotes patients with severe persistent cognitive and clinical deterioration; (2) ‘negative’ or ‘deficit’ schizophrenia, which denotes patients with prominent and persistent primary negative symptoms (e.g. flat affect). An important aspect in better understanding the concept is to approa...

Table of contents

• Cover Page
• Front Matter
• History and Current Definitions of Treatment-Resistant Schizophrenia
• Assessment of Therapy-Resistant Schizophrenia
• Neuropsychology of Treatment-Resistant Schizophrenia
• Genetic Studies in Treatment-Resistant Schizophrenia
• Neuroimaging of Treatment-Resistant Schizophrenia
• Duration of Untreated Psychosis and Premorbid Functioning: Relationship with Treatment Response and Treatment-Resistant Schizophrenia
• Disease Management: Multidimensional Approaches to Incomplete Recovery in Psychosis
• Role of Clozapine in Treatment-Resistant Schizophrenia
• Augmenting Clozapine Response in Treatment-Resistant Schizophrenia
• New Therapeutic Strategies for Resistance to Clozapine and Treatment-Resistant Schizophrenia
• Electroconvulsive Therapy for Treatment-Refractory Schizophrenia
• Treatment of Therapy-Resistant Auditory Verbal Hallucinations in Schizophrenia Patients by Repetitive Transcranial Magnetic Stimulation
• Author Index
• Subject Index