Treatment resistant schizophrenia: Course of brain structure and function Philip D. Harvey, Jennifer B. Rosenthal PII: DOI: Reference:
S0278-5846(16)30023-9 doi: 10.1016/j.pnpbp.2016.02.008 PNP 8890
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
30 October 2015 8 February 2016 21 February 2016
Please cite this article as: Harvey Philip D., Rosenthal Jennifer B., Treatment resistant schizophrenia: Course of brain structure and function, Progress in Neuropsychopharmacology & Biological Psychiatry (2016), doi: 10.1016/j.pnpbp.2016.02.008
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Philip D. Harvey, PhD1,2 Jennifer B. Rosenthal, BS1
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Treatment Resistant Schizophrenia: Course of brain structure and function
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1. University of Miami Miller School of Medicine 2. Research Service, Bruce W. Carter VA Medical Center, Miami, FL
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Address Correspondence to:
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Philip D. Harvey, PhD Department of Psychiatry and Behavioral Sciences University of Miami Miller School of Medicine 1120 NW 14th Street Miami, FL 33136 305-243-1619 (Fax) [email protected]
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Keywords: Schizophrenia, clozapine, treatment resistance
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Abstract Approximately 30% of people with schizophrenia manifest a minimal response to
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conventional and atypical antipsychotic medications and manifest continuous
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symptoms of psychosis, with this condition referred to as “Treatment Resistant
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Schizophrenia (TRS)”. There are several neurobiological consequences of continuous psychosis, including regional cortical atrophy and ventricular
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enlargement. Pharmacological treatments are available for TRS, with at least 1/3 of
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patients responding to treatment with clozapine. In this paper we review the evidence regarding the course of treatment resistant schizophrenia, as well as
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changes in brain structure and function in psychosis and on the possible role of
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clozapine treatment in altering cortical deterioration in patients with TRS.
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Although the majority of patients with schizophrenia experience a beneficial effect from treatment with antipsychotic medications, there exists a substantial minority
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who do not experience a good clinical response. The common term for this subgroup
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of patients is “treatment-resistant” patients, despite the fact that patients who are
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adherent to their treatments are not “resisting” the interventions offered. There are several important issues in the domain of treatment resistant schizophrenia. These
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include the developmental course of treatment resistance, including its onset and
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potential worsening over time. Related to this important topic, the issue of whether there are biological changes, including cortical deterioration, occurring in the
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context of repeated relapses and the development of treatment resistance. This
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question has received substantial attention recently, with several long-term follow-
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up studies of the early course of antipsychotic treatment and the correlates of this course recently published. In the cases where successful pharmacological treatment of treatment resistant symptoms occurs, it is important to understand whether this treatment arrests deterioration in the cortex. We will consider the course of cortical changes and their response to successful and unsuccessful attempts to reduce symptomatic burden treatment resistant schizophrenia. Definition of treatment resistance Although the concept of treatment resistance has been around since the 1960’s (Itil et al., 1966), leading to a variety of attempts at the treatment of this condition, the leading current definition, or the ‘Kane criteria,’ defines treatment resistance with three broad criteria (Kane et al., 1988). First, the patient must fail to respond to three or more adequate trials of antipsychotic treatment within the last
ACCEPTED MANUSCRIPT 4 5 years, including medications from two distinct classes with dosing greater than or equal to the equivalent of 1,000 mg/day of chlorpromazine. With the advent of
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second generation antipsychotic medications, it is now broadly accepted that
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failures to respond to three or more atypical medications or 2 atypical medications plus a conventional medication defines treatment resistance (Suzuki et al., 2011).
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Further, at least with two of the critical psychosis symptoms of conceptual
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disorganization, suspiciousness, hallucinatory behavior, and unusual thought content must score at least 4 (moderate) in severity on a continuous basis. Lastly,
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the patient have evidence of substantial current symptoms despite current optimized treatment to which the patient is adherent, defined as a score greater
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than or equal to 45 on the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962), which would likely be a score on the Positive and Negative Syndrome Scale
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(PANSS;Kay et al., 1987) of 90 or more. Therefore, treatment resistance is generally focused on psychosis and disorganization, and may manifest as complete non-response or minimal benefit to treatment with medications to which the majority of patients have a beneficial response (Tracey et al., 2013). Treatment resistance is not subtle and should be differentiated from partial or incomplete response, where patients experience either moderate improvements with residual or episodic (breakthrough) psychotic symptoms or persistence of a single psychotic symptom, such as delusions or hallucinations, despite successful treatment of their other symptomatic features. In considering treatment resistance, it is also important to ensure that nonresponse is not actually nonadherence, which is prevalent in schizophrenia (Marder,
ACCEPTED MANUSCRIPT 5 2003) and begins at the time of the first episode (Casiero et al., 2012; Robinson et al., 1999). Both relapse after successful treatment or persistent symptoms despite
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treatment may actually be caused by not taking medication at all or by taking it in an
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inconsistent or limited manner. It is challenging to make sure that patients are taking their medications. Prior to designating a patient treatment resistant, it is
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important to evaluate adherence as comprehensively as possible. This would
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include examination of refill patterns, input from informants, and possible observation while hospitalized with an acute exacerbation.
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Because this definition of treatment resistance is chiefly based on clinical symptoms, many have recommended incorporating assessment of psychosocial
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factors, including medication adherence and substance abuse in the definition. For example, Suzuki et al. (2012) suggested also requiring global functional
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impairments defined by the Clinical Global Impression Severity Scale (CGI-S), the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) scale, and/or the Global Assessment of Functioning (GAF). Consideration of everyday functioning and other clinical features of the illness is very important (i.e., motivation, insight, cooperativeness); many patients who symptoms are clinically responsive remain disabled and have multiple elements of poor functional outcome (Strassnig & Harvey, 2014). Treatment resistant patients with current conceptualizations have functional deficits as well as persistent symptoms despite treatment. It also is important to conceptually separate the consideration of impairments in everyday functioning and persistent clinical symptoms. The two do not necessarily overlap. Successful treatment of clinical symptoms does not assure
ACCEPTED MANUSCRIPT 6 disability reduction and functional remission may occur in the presence of persistent psychosis (Harvey & Bellack, 2012). Regardless of the assessment
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strategies used and the factors considered, we agree that patients be considered
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treatment resistant only if both the clinical and functional outcomes are both poor. A concurrently developed conceptualization of treatment resistance was
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focused on just this global and multidimensional impairment. First described by
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Keefe et al. (1987), the “Kraepelinian” conceptualization was focused on catastrophic disability as well as failures in treatment response to antipsychotic
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medications. Those criteria identified a subgroup with wide ranging deficits in everyday functioning, being dependent on others for all of their needs for at least a
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5-year period, while concurrently manifesting no evidence of symptomatic response despite adequate treatment during this period. These patients were
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described as having a greater family history of schizophrenia-related conditions as well as having cortical abnormalities detected with neuroimaging, including asymmetries of cerebral ventricles. We will return to this group when we discuss the neurobiological consequences of persistent treatment resistance on brain structure and function. It is important to note that this conceptualization was developed immediately prior to the re-introduction of clozapine into the US and has largely been supplanted by the definitions of treatment resistance described above. It is of interest, however, that convergence of functional disability and lack of treatment response converges across different conceptions of very poor outcome in schizophrenia.
ACCEPTED MANUSCRIPT 7 Disability in TRS patients may be associated with greater cognitive impairments compared to other patients. For instance, DeBartolomeis et al. (2013) and Frydecka
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et al (2015) reported greater cognitive impairments in TRS patients than in
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treatment responsive patients. Further, negative symptoms were also more severe and associated with TRS status as well. Iasevoli et al. (2015) studied 118 patients
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with TRS and other conditions, finding that TRS patients were considerably more
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impaired on everyday functioning than non-TRS patients with schizophrenia as well as mood and anxiety disordered patients. Both clinical symptoms and cognitive
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performance were considerably worse than in treatment responsive patients, leading the authors to suggest that TRS may be a separate diagnostic entity. Thus,
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multiple previously replicated predictors of poor functional outcome, including cognitive deficits and negative symptoms (Galderisi et al., 2014; Strassnig et al.,
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2015), accompany the TRS syndrome. Origins of treatment resistance. Considerable evidence suggests that most patients with schizophrenia manifest a positive response to their first treatment with antipsychotic medication (Robinson et al.,1999b). This response appears quite robust and affects as many as 90% of patients within their first months of treatment, according to the results of the first Hillside Hospital study. Recent studies have suggested that there may be more variability in treatment response than suggested by the Hillside Hospital studies. For instance, Nordon et al. (2014) found that in a sample of 467 patients, 249 had a good clinical response and 133 were found to be remaining mildly ill after treatment. Only 4.9% remained severely ill. Although Nordon et al., consider their residually mildly ill group to be “non-responsive”,
ACCEPTED MANUSCRIPT 8 those cases would not meet the current criteria for TRS because their symptoms are too mild. Another group with milder initial baseline symptoms (n=62) had an initial
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response but did not sustain it over time. These results are consistent with those by
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Levine and Rabinowitz (2010), who found that mildly ill patients often did not manifest good treatment response. Further, in their large-scale clinical trial
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(n>400), there were about 20% of cases whose treatment response was minimal
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enough at 6 months to consider them as potentially TRS. In a follow-up study of a national sample of psychiatric admissions (n=2290), Levine et al. (2011) reported
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that approximately 12% of patients manifested a refractory course starting at the first episode, with another 30% or so who developed a refractory course over time.
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Both the rate and time course of treatment response show evidence of worsening after the first relapse with as many as 1/3 of patients showing evidence of treatment
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resistance within the first five years of illness (Levine et al., 2011; Lieberman et al., 1996). Thus, treatment resistance appears to develop after at last one or more successful treatments in the majority of TRS cases over time, approximately doubling to tripling in prevalence compared to the first episode over the lifetime course of the illness. The origins appear to be complex, from an interaction of psychosis, antipsychotic treatment, treatment discontinuation, relapse, and retreatment, the neurobiological consequences of which will be explored below. The suggestion that TRS is a separate syndrome is not contradicted by the development of non-response over time, as most patients do not develop TRS. Persistent Negative Symptoms and their Relationship to Treatment Resistance. There has been considerable interest in a condition conceptually
ACCEPTED MANUSCRIPT 9 related to treatment resistance, persistent negative symptoms (Buchanan et al., 2007). Persistent negative symptoms are typically defined as negative symptoms
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that persist after at least partial treatment response for psychotic or disorganized
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symptoms, often referred to as the deficit syndrome ( Carpenter et al., 1988; 1999; Kirkpatrick & Buchanan, 1989; Kirkpatrick et al., 1989). Almost one-third of
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patients who demonstrate notable improvements in psychosis and disorganization
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with antipsychotic treatment have persistent negative symptoms, with these symptoms also manifesting minimal response to any interventions attempted to
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date (Kirkpatrick et al., 2000). Interestingly, there is little evidence to suggest that persistent negative symptoms are improved through the use of treatments, such as
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clozapine, that have efficacy for global treatment resistance. This situation has led to attempts to develop treatments and outcomes measures targeted specifically at
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these symptoms (See Kirkpatrick et al., 2006; and Special Issue of Schizophrenia Research, 2013, Volume 150). Some studies have shown that persistent negative symptoms in people with chronic schizophrenia are more strongly associated with social outcomes than with other elements of everyday functioning such as employment or independence in residential functioning (Strassnig et al., 2015). It is likely, however, that persistent negative symptoms can also have an effect on other domains of everyday functioning in a longitudinal manner. Poor motivation and reduced sensitivity to rewards at the current time can easily to impairments in employment and homeless later in time (Ventura et al., 2015). Another clinical difference between persistent negative symptoms and global treatment resistance is the early course of these symptoms. As noted above, the full
ACCEPTED MANUSCRIPT 10 syndrome of treatment resistance is present in a minority of patients at the first episode of psychosis. However, negative symptoms can be prominent at the time of
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the first episode and persistent negative symptoms following otherwise successful
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pharmacological treatment of psychosis at the time of the first episode can have wide-ranging functional consequences. In specific, Ventura et al. (2015) reported
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that negative symptom severity after 1 year of illness was associated with multiple
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elements of impaired everyday functioning 7 years later. Thus, persistent negative symptoms early in the life-course of schizophrenia may have quite adverse long-
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term consequences that are not as obvious or detectable when the illness is fully developed.
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Neurotoxic effects of Persistent psychosis. One of the long-term controversies in the treatment and study of schizophrenia has been whether psychosis exerts a toxic
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effect on the brain. This idea partially originated from the observation that the global outcome of schizophrenia has appeared to improve following the availability of antipsychotic medication and the standard of care evolving into the early treatment of psychosis. An influential review paper published by Wyatt (1991), summarized data regarding outcomes of schizophrenia from the “pre-neuroleptic” era and afterwards. The general conclusion was that early intervention with antipsychotic medications led to improvements in long-term outcomes. These outcomes included reduction of the severity of psychotic symptoms after receiving antipsychotic medications, time in spent as an inpatient in hospital settings, and total time over the lifespan experiencing psychotic symptoms. All of these indices
ACCEPTED MANUSCRIPT 11 seem to reflect less severity during the period where antipsychotic medications were available from the onset of the illness.
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This conclusion was supported as well by analyses of data from studies
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where first episode patients were treated as inpatients but did not receive antipsychotic medications (Wyatt and Henter 1998). In the early days of
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antipsychotic medication treatment, particularly when the only medications
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available were conventional medications with elevated risks of lifelong movement disorders, there was a reluctance to treat psychosis with antipsychotic medication
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as soon as it was detected. As a result, patients with psychosis were often admitted to a hospital and treated until discharge without the use of antipsychotic
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medications. Obviously, these would be patients with lower levels of psychosis and agitation. These studies suggested that patients who were not treated with
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antipsychotic medications during an entire inpatient treatment episode had less severe symptoms at the time of admission than patients who were treated with antipsychotic medications during their inpatient stay. Importantly, their long-term outcomes were worse than patients treated as inpatients with antipsychotic medications at their first admission, despite the greater severity of severity of psychosis on the part of the antipsychotic treated patients (Wyatt et al., 1997). These results and many studies since then have led to the conception that psychosis has a progressive course (DeLisi et al., 1997) and have spurred efforts to detect and reduce the duration of untreated psychosis at the outset of psychotic episodes. There have been a series of different studies that focused on the course of psychosis following the first episode. One research group, based in Utrecht in the
ACCEPTED MANUSCRIPT 12 Netherlands, has followed first admission patients over their first years of illness and examined the interaction between treatment, relapse, and re-treatment across a
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large number of different possible outcomes (Cahn et al., 2006; van Haren et al.,
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2007; 2011). These outcomes have included changes in cortical thickness, overall brain volume, hippocampal volumes, and focal gray matter changes. All of these
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alterations occurred early in the illness, were associated with more relapses, and
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were worse in cases who received treatment with conventional antipsychotic medications after their relapses. Interestingly, the change appeared to be associated
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primarily with events after the onset of the illness, because duration of untreated psychosis did not appear to impact 5-year outcomes in this large sample (Boonstra
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et al., 2011).
The findings of volume loss early in the illness associated with more severe
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illness and more intensive treatment has been confirmed in independent studies, although some of the results are inconsistent. These inconsistencies are least partially due to the fact that in some regions conventional antipsychotic medications are rarely used in younger patients, precluding comparisons of conventional vs. atypical medications as a treatment. Also, clozapine treated patients are examined in some studies, but were not included in others. The rate of clozapine treatment in early-course patients is minimal. Thus, understanding the influences of confounding factors is important. Unresolved issues include whether the factors predicting more adverse neurobiological and functional outcomes include the number of relapses and re-treatments, the duration of the relapses, the intensity of treatment after relapse, or the severity of symptoms during the relapses. However, the evidence is
ACCEPTED MANUSCRIPT 13 clear and consistent that relapse and re-treatment early in the course of illness in schizophrenia is associated with risk for adverse cortical changes.
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A longitudinal study of first episode patients who had received successful
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treatment for a first episode of schizophrenia indicated that the total duration of time spent experiencing psychosis during relapses predicted brain volume loss
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(Andreasen et al., 2013). Interestingly, symptom severity during or between
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relapses did not predict loss of cortical volume and the intensity of treatment, indexed by total antipsychotic exposure during the entire follow-up period, also
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predicted loss of cortical gray matter. These data are among several studies that have shown that, on average, total antipsychotic treatment exposures are correlated
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with cortical volume loss. A systematic review suggested that this effect held up across studies, with several limitations (Fusar-Poli et al., 2013). The most major of
compare:
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these limitations is that the authors of this review were not able to systematically
a. Typical vs. atypical antipsychotic treatment b. Treatment response: responsive vs. resistant c. Treatment adherence. These are clearly major issues. If positive treatment response, meaning less psychosis over time, is associated with less volume loss then the suggestion would be that nonresponsive patients should have their medications reduced or stopped. Nonadherent patients are not exposed to medications because they do not take them regardless of their symptom severity. Thus, if excessive psychosis associated with nonadherence leads to increased medication doses prescribed, the increased
ACCEPTED MANUSCRIPT 14 dose of medication would still have no association with cortical atrophy because there was no real medication exposure. This is a major issue with all studies that
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correlate medication doses that are prescribed with objective outcome variables
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such as cortical changes in the absence of information regarding medication actually taken by the patients.
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Given these interpretive problems, the most critical question to be answered
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is whether positive treatment response and lack of relapses predicts a better course of brain integrity during and across antipsychotic treatments. This question can
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only be answering by comparing patients receiving the same treatment who vary in their overall clinical response and examining differential brain changes in those two
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groups. Neuroimaging studies reviewed below have addressed the possible beneficial effects of clozapine treatment on cortical structure and function, in
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contrast to the potential adverse effects of treatment with higher doses of other medications. However, it is clear from later studies as well as the early CT scan work that persistent symptoms confer risk of cortical changes and that concurrent treatment with conventional medications or atypical antpsychotics other than clozapine at best provides no protection against cortical changes. Some studies of early course patients have provided evidence that those patients who show progressive cortical changes also manifest cognitive deterioration as well. In specific, Ho et al. (2003) reported a correlation between progressive loss of gray matter and worsening in executive functioning. In specific, a 3-year follow-up of first episode patients found variations in changes both white and gray matter across individuals. Those individuals who lost volume in both
ACCEPTED MANUSCRIPT 15 frontal lobe white and gray matter showed evidence of deterioration in their executive functioning. Those who lost only white matter had evidence of increased
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negative symptoms, suggesting different risk factors for the development of
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persistent negative symptoms and everyday disability associated with worsening cognitive performance. Given the prominence of cognitive deficits in treatment
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resistant patients, such cognitive changes may contribute to poor outcomes over
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time. In a study examining first episode patients, Lappin et al. (2013) found that increases in hippocampal volumes after treatment of a first psychotic episode led to
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better cognitive and functional outcomes, suggesting bidirectional effects of volume changes in the CNS during psychosis.
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Multiple neuroimaging studies, reviewed in Nakajima (2015), have compared both healthy controls and treatment responsive patients to TRS patients. They have
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reported both alterations in cortical thickness and volumes as well as connectivity differences between these groups. As described below, imaging has also been used to predict treatment response and to characterize functional brain changes following treatment with clozapine. In addition, several studies using functional imaging have suggested reduced metabolism in the prefrontal cortex and increases in basal ganglia metabolism in TRS patients ( e.g., Molina et al., 1997). Progression of Cortical and Functional Deterioration in Treatment Resistant Patients. There has surprisingly been little research on the course of cortical and functional change in chronic treatment resistant patients. This may be due to funding priorities, where a focus on early intervention and prevention has led to a
ACCEPTED MANUSCRIPT 16 shift in funding away from studying cases with established illness. Partially this situation may be due to ethical and human subjects concerns, where very impaired
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and psychotic patients may not be able to provide informed consent to participate in
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neuroimaging research.
In one of the first imaging studies addressing progressive cortical change in
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treatment resistant patients, Davis et al. (1998) reported that Kraepelinian patients
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manifested left-sided ventricular enlargement compared to treatment responsive patients followed over the same 5-year follow-up period. The most important part
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of this study is that the major differences between the treatment resistant (Kraepelinian) patients and the treatment responsive patients was symptoms alone.
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Both groups were receiving treatment with conventional antipsychotic medications and both had a history of extended prior hospital stays. Total spent in the hospital
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over the lifetime was correlated with the rate of ventricular enlargement in the Kraepelinian patients only.
This study suggested the role of continued psychotic symptoms despite treatment as a risk factor for ventricular changes and, by inference, cortical atrophy. An MRI study of 24 patients with schizophrenia with an average four-year follow-up also reported evidence of decreases in cortical volume in a number of critical brain regions when compared to healthy controls of a similar age (Mathalon et al.,2001) . Broadly consistent with the results of the Davis et al study, averaged severity of psychopathology as well as the proportion of time spent hospitalized in the fouryear follow-up period was correlated with decreases in brain volumes, suggesting
ACCEPTED MANUSCRIPT 17 that “total dose” of psychosis was associated with risk for cortical atrophy. Similar findings were reported by Gur et al. (1998).
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Some more clinically focused studies have examined the predictors of
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cognitive and functional decline in chronic schizophrenia patients with extended hospital stays. In a series of studies of the same large sample of chronically
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hospitalized inpatients, the severity of psychotic symptoms, despite on-going
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antipsychotic treatment, was found to predict the risk for cognitive and functional decline. In the first study (Harvey et al.,1999) severity of psychosis despite
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antipsychotic treatment at baseline predicted risk for cognitive and functional decline over a 36 month period. In a 6-year follow-up in a larger sample (Harvey et
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al., 2003; n=424), the course of cognitive functioning predicted the course of functional disability. Interestingly, and consistent with the results of the earlier,
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shorter study, patients whose psychotic symptoms were stably high or worsened during the follow-up period showed the greatest risk for cognitive decline. The declines seen in these patients did not resemble those seen in a sample of patients with Alzheimer’s disease followed up over the same time period (Friedman et al., 2001). Psychosis despite adequate conventional antipsychotic treatment was associated with cognitive and functional decline over time. Because of the age and baseline levels of impairment in these patients, imaging studies were not possible. Studying patients over the age of 50, Fucetola et al., (2000) reported a specific decline in executive functioning beyond that seen in healthy individuals. Similarly, Granholm et al. (2010) reported reduced performance-related benefits from retesting in older patients with schizophrenia compared to healthy individuals,
ACCEPTED MANUSCRIPT 18 while Bowie et al. (2008) reported that high-load information processing tests were more sensitive to age-related declines than traditional neuropsychological measures
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in a community dwelling older sample. Finally, two follow-up studies of ambulatory
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patients (Harvey et al., 2010; Reichenberg et al., 2014) found that cognitive and functional decline was detected in patients with a history of previous institutional
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stay (generally due to treatment resistance) and was absent in patients who never
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experienced such an extended stay.
Clozapine for treatment resistant schizophrenia. Clozapine has been proven in
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multiple studies to have efficacy for the reduction of psychotic symptoms in patients who have failed repeated treatments with other medications. After the conclusive
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demonstration of the efficacy of the medication in treatment-resistant patients compared to conventional antipsychotic treatments (Kane et al, 1988), clozapine
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treatment was re-introduced to the US. Multiple studies have shown that in truly treatment resistant patients, clozapine is superior to other atypical antipsychotic medications, including those that are chemically quite similar such as olanzapine. In the large-scale CATIE study, clozapine again demonstrated superiority to other medications after prospective confirmation of treatment resistance (McEvoy et al., 2006). Clozapine’s potential side effects include functional bone marrow suppression and agranulocytosis. These risks necessitate leukocyte and neutrophil count monitoring throughout the duration of treatment. Other potential side effects include diabetic ketoacidosis (DKA), gastrointestinal (GI) hypomotility, and myocarditis. Furthermore, Ahmed et al. (2008) demonstrated that almost half of the
ACCEPTED MANUSCRIPT 19 clozapine patients in his study developed metabolic syndrome. Seizure threshold is lowered with clozapine treatment, which is actually a benefit in some situations, as
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we will see in our upcoming discussion of ECT for clozapine nonresponders. There
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are another of additional side effects as well (Miller and Buckley, 2014). Despite the common characterization of clozapine as a medication with a
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substantial side effect burden, as described above, clozapine has been found to be
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the antipsychotic drug treatment associated with the lowest mortality. In a whole nation study, Tiihonen et al. (2009) studied mortality in a cohort of 66,881
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schizophrenia patients in Finland, and found that clozapine demonstrated the lowest all cause mortality of any antipsychotic medications. This phenomenon is
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likely due to suicide risk reduction, which makes several critical points. Suicide is a major problem for patients with schizophrenia and strikes over the entire lifetime
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course. Weight gain and metabolic syndrome develops gradually and can be detected and treated. Suicide is often precipitous and not immediately predictable or preventable. Thus, other than agranulcytosis, which is rare (3%) and generally (but not always) occurs early in the course of treatment, clozapine side effects are only dangerous if unmanaged. Does clozapine prevent or reverse cortical deterioration? The relationship between clozapine treatment in treatment resistant patients and changes brain functioning is an under researched topic, and a few studies have come to conflicting conclusions. These mixed results run the entire range of possible outcomes, including studies that have demonstrated that clozapine treatment generically reduces change, reduces it only in responders, or does not have an effect
ACCEPTED MANUSCRIPT 20 at all. In the van Haren et al. (2007) study relapses in schizophrenia patients were associated with decreases in gray matter density in the left superior frontal area
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(Broadmann areas 9/10), left superior temporal gyrus (Broadmann area 42), right
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caudate nucleus, and right thalamus, patients receiving clozapine treatment showed attenuated effects. In fact, increases in the amount of clozapine administered to
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patients narrowed the difference in superior frontal grey matter density between
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schizophrenic patients and healthy controls. It is worth noting that this affect was associated with clozapine treatment but not treatment with typical antipsychotic
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medication. These results are congruent with a prior study that reported progressive global grey matter loss in patients treated with typical antipsychotics,
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but not atypical antipsychotics (Lieberman et al., 2005). However, this was a study of olanzapine treatment in first episode patients, so the comparisons are not direct.
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Van Haren et al. (2011) showed that higher clozapine doses were associated with less thinning in many frontal areas and the right cingulate. Nonetheless, patients receiving clozapine had more pronounced cortical thinning in the left superior temporal cortex. The small sample sizes in this study for clozapine treated patients may be associated with these apparently inconsistent findings. Molina et al. (2005) found that clozapine treatment was associated with grey matter increases and white matter decreases in the parietal and occipital lobes. The greatest gain of gray matter was seen in the occipital region. They also found that frontal grey matter increased in a group of chronic treatment-resistant patients treated with clozapine. The gain in gray matter was more pronounced in the group treated with clozapine than the previously treatment-naive group treated with
ACCEPTED MANUSCRIPT 21 risperidone. Although this may be due to the greater atrophy at baseline, their results suggest that such atrophy may be reversed with clozapine treatment.
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On the contrary, the results of Ahmed et al. (2015) suggest that clozapine
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treatment is not correlated with arrest or reversal of brain volume loss or cortical thinning. In that investigation, patients with TRS as a group had more cortical
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thinning than HC, particularly in the left medial prefrontal cortex. Patients with the
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least thinning were the most likely to have a positive clinical response to clozapine. But because most patients treated with clozapine in their study improved clinically,
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the loss of grey matter appears associated with an ongoing neurotoxic pathophysiology that is not necessarily associated with the concurrent presence of
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uncontrolled psychotic symptoms. So, in the case of the patients in the Ahmed et al., study, clozapine- associated clinical improvement did not lead to attenuation of
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cortical atrophy during the followup period. These studies reviewed above are naturalistic studies that often have small sample sizes and are limited by the fact that they are post hoc studies. The weight of the evidence suggests that cortical atrophy is associated with uncontrolled psychosis during period of relapse. Arrest of a cortical atrophic process or reversal of previous atrophy with clozapine treatment is a much more inconsistent finding and is based on a much smaller evidence base. What is clear, however, is that relapses have neurotoxic effects that may include causing cognitive and functional decline. Clozapine treatment has not been implicated in causing progressive volume loss in the cortex, such that it appears to be the best treatment strategy for patients who have developed treatment resistance. Whether long-term treatment with
ACCEPTED MANUSCRIPT 22 clozapine has the potential to reverse previous cortical changes is a question for further research.
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Conclusions.
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Persistent psychosis and relapse followed by retreatment have been shown to have both neurobiological and cognitive and behavioral consequences. Treatment
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resistance doubles in its prevalence following the first episode of schizophrenia and
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relapses and re-treatments are extremely common even I responsive cases. Cortical atrophy is clearly demonstrated as a function of psychosis and treatment burden,
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including in cases who manifest treatment resistant schizophrenia. Clozapine is the only treatment with demonstrated efficacy for treatment resistant schizophrenia
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and there are multiple benefits of clozapine treatment in those cases whose response is positive. Clearly the search of other treatments to benefit the 20% of all
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patients with schizophrenia who fail to benefit from all available treatments (“Ultra Resistant Schizophrenia: URS”; Nakajima et al., 2015) is a priority.
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Ahmed M, Cannon DM, Scanlon K, et al. Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment. Neuropsychopharmacology 2015; 30: 2409-2417.
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Ahmed M, Hussain J, O’Brien SM, et al. Prevalence and associations of the metablic syndrome among schizophrenia patients prescribed clozapine. Ir J Med Sci 2008; 177:205-210
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Boonstra G, Cahn W, Schnack HG, et al Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change. Schizophr Res 2011; 132:84-90.
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ACCEPTED MANUSCRIPT 25 Harvey PD, Bertisch H, Friedman JI, et al. The course of functional decline in geriatric patients with schizophrenia: Cognitive-functional and clinical symptoms as determinants of change. . Am J Geriatr Psychiatry 2003; 11:610-619.
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ACCEPTED MANUSCRIPT 26 Levine SZ, Lurie I, Kohn R, and Levav I. Trajectories of the course of schizophrenia: from progressive deterioration to amelioration over three decades. Schizophr Res. 2011 Mar;126:184-91
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Miller BJ & Buckley PF. Medical and psychiatric comorbidities: Complicating treatment expectations. In PF Buckley and F Gaughran (Eds). Treatment refractory schizophrenia: A clinical conundrum pp. 45-64. New York: Springer, 2014. Molina Rodriguez V, Andree RM, Castejon, M.J., et al. Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study. Psychiat Res 1997; 76: 51–61. Molina Rodriguez V, Reig S, Sanz J, et al. Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia. Schizophr Res 2005; 80, 61–71. Nakajima S, Takeuchi H, Plitman E, Et al. Neuroimaging findings in treatmentresistant schizophrenia: A systematic review: Lack of neuroimaging correlates of treatment-resistant schizophrenia. Schizophr Res 2015; 164(1-3):164-75 Nordon S, Rouillon F, Azorin JM, et al. Trajectories of antipsychotic response in drug-naive schizophrenia patients: results from the 6-month ESPASS follow-up study. Acta Psychiatr Scand 2014: 129: 116–125
ACCEPTED MANUSCRIPT 27 Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962; 10: 799–812.
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S0278-5846(16)30023-9 doi: 10.1016/j.pnpbp.2016.02.008 PNP 8890
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
30 October 2015 8 February 2016 21 February 2016
Please cite this article as: Harvey Philip D., Rosenthal Jennifer B., Treatment resistant schizophrenia: Course of brain structure and function, Progress in Neuropsychopharmacology & Biological Psychiatry (2016), doi: 10.1016/j.pnpbp.2016.02.008
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Philip D. Harvey, PhD1,2 Jennifer B. Rosenthal, BS1
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Treatment Resistant Schizophrenia: Course of brain structure and function
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1. University of Miami Miller School of Medicine 2. Research Service, Bruce W. Carter VA Medical Center, Miami, FL
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Address Correspondence to:
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Philip D. Harvey, PhD Department of Psychiatry and Behavioral Sciences University of Miami Miller School of Medicine 1120 NW 14th Street Miami, FL 33136 305-243-1619 (Fax) [email protected]
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Keywords: Schizophrenia, clozapine, treatment resistance
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Abstract Approximately 30% of people with schizophrenia manifest a minimal response to
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conventional and atypical antipsychotic medications and manifest continuous
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symptoms of psychosis, with this condition referred to as “Treatment Resistant
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Schizophrenia (TRS)”. There are several neurobiological consequences of continuous psychosis, including regional cortical atrophy and ventricular
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enlargement. Pharmacological treatments are available for TRS, with at least 1/3 of
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patients responding to treatment with clozapine. In this paper we review the evidence regarding the course of treatment resistant schizophrenia, as well as
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changes in brain structure and function in psychosis and on the possible role of
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clozapine treatment in altering cortical deterioration in patients with TRS.
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Although the majority of patients with schizophrenia experience a beneficial effect from treatment with antipsychotic medications, there exists a substantial minority
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who do not experience a good clinical response. The common term for this subgroup
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of patients is “treatment-resistant” patients, despite the fact that patients who are
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adherent to their treatments are not “resisting” the interventions offered. There are several important issues in the domain of treatment resistant schizophrenia. These
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include the developmental course of treatment resistance, including its onset and
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potential worsening over time. Related to this important topic, the issue of whether there are biological changes, including cortical deterioration, occurring in the
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context of repeated relapses and the development of treatment resistance. This
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question has received substantial attention recently, with several long-term follow-
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up studies of the early course of antipsychotic treatment and the correlates of this course recently published. In the cases where successful pharmacological treatment of treatment resistant symptoms occurs, it is important to understand whether this treatment arrests deterioration in the cortex. We will consider the course of cortical changes and their response to successful and unsuccessful attempts to reduce symptomatic burden treatment resistant schizophrenia. Definition of treatment resistance Although the concept of treatment resistance has been around since the 1960’s (Itil et al., 1966), leading to a variety of attempts at the treatment of this condition, the leading current definition, or the ‘Kane criteria,’ defines treatment resistance with three broad criteria (Kane et al., 1988). First, the patient must fail to respond to three or more adequate trials of antipsychotic treatment within the last
ACCEPTED MANUSCRIPT 4 5 years, including medications from two distinct classes with dosing greater than or equal to the equivalent of 1,000 mg/day of chlorpromazine. With the advent of
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second generation antipsychotic medications, it is now broadly accepted that
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failures to respond to three or more atypical medications or 2 atypical medications plus a conventional medication defines treatment resistance (Suzuki et al., 2011).
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Further, at least with two of the critical psychosis symptoms of conceptual
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disorganization, suspiciousness, hallucinatory behavior, and unusual thought content must score at least 4 (moderate) in severity on a continuous basis. Lastly,
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the patient have evidence of substantial current symptoms despite current optimized treatment to which the patient is adherent, defined as a score greater
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than or equal to 45 on the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962), which would likely be a score on the Positive and Negative Syndrome Scale
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(PANSS;Kay et al., 1987) of 90 or more. Therefore, treatment resistance is generally focused on psychosis and disorganization, and may manifest as complete non-response or minimal benefit to treatment with medications to which the majority of patients have a beneficial response (Tracey et al., 2013). Treatment resistance is not subtle and should be differentiated from partial or incomplete response, where patients experience either moderate improvements with residual or episodic (breakthrough) psychotic symptoms or persistence of a single psychotic symptom, such as delusions or hallucinations, despite successful treatment of their other symptomatic features. In considering treatment resistance, it is also important to ensure that nonresponse is not actually nonadherence, which is prevalent in schizophrenia (Marder,
ACCEPTED MANUSCRIPT 5 2003) and begins at the time of the first episode (Casiero et al., 2012; Robinson et al., 1999). Both relapse after successful treatment or persistent symptoms despite
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treatment may actually be caused by not taking medication at all or by taking it in an
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inconsistent or limited manner. It is challenging to make sure that patients are taking their medications. Prior to designating a patient treatment resistant, it is
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important to evaluate adherence as comprehensively as possible. This would
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include examination of refill patterns, input from informants, and possible observation while hospitalized with an acute exacerbation.
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Because this definition of treatment resistance is chiefly based on clinical symptoms, many have recommended incorporating assessment of psychosocial
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factors, including medication adherence and substance abuse in the definition. For example, Suzuki et al. (2012) suggested also requiring global functional
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impairments defined by the Clinical Global Impression Severity Scale (CGI-S), the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) scale, and/or the Global Assessment of Functioning (GAF). Consideration of everyday functioning and other clinical features of the illness is very important (i.e., motivation, insight, cooperativeness); many patients who symptoms are clinically responsive remain disabled and have multiple elements of poor functional outcome (Strassnig & Harvey, 2014). Treatment resistant patients with current conceptualizations have functional deficits as well as persistent symptoms despite treatment. It also is important to conceptually separate the consideration of impairments in everyday functioning and persistent clinical symptoms. The two do not necessarily overlap. Successful treatment of clinical symptoms does not assure
ACCEPTED MANUSCRIPT 6 disability reduction and functional remission may occur in the presence of persistent psychosis (Harvey & Bellack, 2012). Regardless of the assessment
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strategies used and the factors considered, we agree that patients be considered
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treatment resistant only if both the clinical and functional outcomes are both poor. A concurrently developed conceptualization of treatment resistance was
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focused on just this global and multidimensional impairment. First described by
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Keefe et al. (1987), the “Kraepelinian” conceptualization was focused on catastrophic disability as well as failures in treatment response to antipsychotic
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medications. Those criteria identified a subgroup with wide ranging deficits in everyday functioning, being dependent on others for all of their needs for at least a
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5-year period, while concurrently manifesting no evidence of symptomatic response despite adequate treatment during this period. These patients were
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described as having a greater family history of schizophrenia-related conditions as well as having cortical abnormalities detected with neuroimaging, including asymmetries of cerebral ventricles. We will return to this group when we discuss the neurobiological consequences of persistent treatment resistance on brain structure and function. It is important to note that this conceptualization was developed immediately prior to the re-introduction of clozapine into the US and has largely been supplanted by the definitions of treatment resistance described above. It is of interest, however, that convergence of functional disability and lack of treatment response converges across different conceptions of very poor outcome in schizophrenia.
ACCEPTED MANUSCRIPT 7 Disability in TRS patients may be associated with greater cognitive impairments compared to other patients. For instance, DeBartolomeis et al. (2013) and Frydecka
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et al (2015) reported greater cognitive impairments in TRS patients than in
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treatment responsive patients. Further, negative symptoms were also more severe and associated with TRS status as well. Iasevoli et al. (2015) studied 118 patients
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with TRS and other conditions, finding that TRS patients were considerably more
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impaired on everyday functioning than non-TRS patients with schizophrenia as well as mood and anxiety disordered patients. Both clinical symptoms and cognitive
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performance were considerably worse than in treatment responsive patients, leading the authors to suggest that TRS may be a separate diagnostic entity. Thus,
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multiple previously replicated predictors of poor functional outcome, including cognitive deficits and negative symptoms (Galderisi et al., 2014; Strassnig et al.,
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2015), accompany the TRS syndrome. Origins of treatment resistance. Considerable evidence suggests that most patients with schizophrenia manifest a positive response to their first treatment with antipsychotic medication (Robinson et al.,1999b). This response appears quite robust and affects as many as 90% of patients within their first months of treatment, according to the results of the first Hillside Hospital study. Recent studies have suggested that there may be more variability in treatment response than suggested by the Hillside Hospital studies. For instance, Nordon et al. (2014) found that in a sample of 467 patients, 249 had a good clinical response and 133 were found to be remaining mildly ill after treatment. Only 4.9% remained severely ill. Although Nordon et al., consider their residually mildly ill group to be “non-responsive”,
ACCEPTED MANUSCRIPT 8 those cases would not meet the current criteria for TRS because their symptoms are too mild. Another group with milder initial baseline symptoms (n=62) had an initial
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response but did not sustain it over time. These results are consistent with those by
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Levine and Rabinowitz (2010), who found that mildly ill patients often did not manifest good treatment response. Further, in their large-scale clinical trial
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(n>400), there were about 20% of cases whose treatment response was minimal
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enough at 6 months to consider them as potentially TRS. In a follow-up study of a national sample of psychiatric admissions (n=2290), Levine et al. (2011) reported
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that approximately 12% of patients manifested a refractory course starting at the first episode, with another 30% or so who developed a refractory course over time.
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Both the rate and time course of treatment response show evidence of worsening after the first relapse with as many as 1/3 of patients showing evidence of treatment
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resistance within the first five years of illness (Levine et al., 2011; Lieberman et al., 1996). Thus, treatment resistance appears to develop after at last one or more successful treatments in the majority of TRS cases over time, approximately doubling to tripling in prevalence compared to the first episode over the lifetime course of the illness. The origins appear to be complex, from an interaction of psychosis, antipsychotic treatment, treatment discontinuation, relapse, and retreatment, the neurobiological consequences of which will be explored below. The suggestion that TRS is a separate syndrome is not contradicted by the development of non-response over time, as most patients do not develop TRS. Persistent Negative Symptoms and their Relationship to Treatment Resistance. There has been considerable interest in a condition conceptually
ACCEPTED MANUSCRIPT 9 related to treatment resistance, persistent negative symptoms (Buchanan et al., 2007). Persistent negative symptoms are typically defined as negative symptoms
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that persist after at least partial treatment response for psychotic or disorganized
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symptoms, often referred to as the deficit syndrome ( Carpenter et al., 1988; 1999; Kirkpatrick & Buchanan, 1989; Kirkpatrick et al., 1989). Almost one-third of
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patients who demonstrate notable improvements in psychosis and disorganization
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with antipsychotic treatment have persistent negative symptoms, with these symptoms also manifesting minimal response to any interventions attempted to
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date (Kirkpatrick et al., 2000). Interestingly, there is little evidence to suggest that persistent negative symptoms are improved through the use of treatments, such as
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clozapine, that have efficacy for global treatment resistance. This situation has led to attempts to develop treatments and outcomes measures targeted specifically at
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these symptoms (See Kirkpatrick et al., 2006; and Special Issue of Schizophrenia Research, 2013, Volume 150). Some studies have shown that persistent negative symptoms in people with chronic schizophrenia are more strongly associated with social outcomes than with other elements of everyday functioning such as employment or independence in residential functioning (Strassnig et al., 2015). It is likely, however, that persistent negative symptoms can also have an effect on other domains of everyday functioning in a longitudinal manner. Poor motivation and reduced sensitivity to rewards at the current time can easily to impairments in employment and homeless later in time (Ventura et al., 2015). Another clinical difference between persistent negative symptoms and global treatment resistance is the early course of these symptoms. As noted above, the full
ACCEPTED MANUSCRIPT 10 syndrome of treatment resistance is present in a minority of patients at the first episode of psychosis. However, negative symptoms can be prominent at the time of
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the first episode and persistent negative symptoms following otherwise successful
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pharmacological treatment of psychosis at the time of the first episode can have wide-ranging functional consequences. In specific, Ventura et al. (2015) reported
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that negative symptom severity after 1 year of illness was associated with multiple
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elements of impaired everyday functioning 7 years later. Thus, persistent negative symptoms early in the life-course of schizophrenia may have quite adverse long-
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term consequences that are not as obvious or detectable when the illness is fully developed.
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Neurotoxic effects of Persistent psychosis. One of the long-term controversies in the treatment and study of schizophrenia has been whether psychosis exerts a toxic
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effect on the brain. This idea partially originated from the observation that the global outcome of schizophrenia has appeared to improve following the availability of antipsychotic medication and the standard of care evolving into the early treatment of psychosis. An influential review paper published by Wyatt (1991), summarized data regarding outcomes of schizophrenia from the “pre-neuroleptic” era and afterwards. The general conclusion was that early intervention with antipsychotic medications led to improvements in long-term outcomes. These outcomes included reduction of the severity of psychotic symptoms after receiving antipsychotic medications, time in spent as an inpatient in hospital settings, and total time over the lifespan experiencing psychotic symptoms. All of these indices
ACCEPTED MANUSCRIPT 11 seem to reflect less severity during the period where antipsychotic medications were available from the onset of the illness.
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This conclusion was supported as well by analyses of data from studies
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where first episode patients were treated as inpatients but did not receive antipsychotic medications (Wyatt and Henter 1998). In the early days of
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antipsychotic medication treatment, particularly when the only medications
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available were conventional medications with elevated risks of lifelong movement disorders, there was a reluctance to treat psychosis with antipsychotic medication
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as soon as it was detected. As a result, patients with psychosis were often admitted to a hospital and treated until discharge without the use of antipsychotic
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medications. Obviously, these would be patients with lower levels of psychosis and agitation. These studies suggested that patients who were not treated with
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antipsychotic medications during an entire inpatient treatment episode had less severe symptoms at the time of admission than patients who were treated with antipsychotic medications during their inpatient stay. Importantly, their long-term outcomes were worse than patients treated as inpatients with antipsychotic medications at their first admission, despite the greater severity of severity of psychosis on the part of the antipsychotic treated patients (Wyatt et al., 1997). These results and many studies since then have led to the conception that psychosis has a progressive course (DeLisi et al., 1997) and have spurred efforts to detect and reduce the duration of untreated psychosis at the outset of psychotic episodes. There have been a series of different studies that focused on the course of psychosis following the first episode. One research group, based in Utrecht in the
ACCEPTED MANUSCRIPT 12 Netherlands, has followed first admission patients over their first years of illness and examined the interaction between treatment, relapse, and re-treatment across a
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large number of different possible outcomes (Cahn et al., 2006; van Haren et al.,
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2007; 2011). These outcomes have included changes in cortical thickness, overall brain volume, hippocampal volumes, and focal gray matter changes. All of these
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alterations occurred early in the illness, were associated with more relapses, and
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were worse in cases who received treatment with conventional antipsychotic medications after their relapses. Interestingly, the change appeared to be associated
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primarily with events after the onset of the illness, because duration of untreated psychosis did not appear to impact 5-year outcomes in this large sample (Boonstra
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et al., 2011).
The findings of volume loss early in the illness associated with more severe
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illness and more intensive treatment has been confirmed in independent studies, although some of the results are inconsistent. These inconsistencies are least partially due to the fact that in some regions conventional antipsychotic medications are rarely used in younger patients, precluding comparisons of conventional vs. atypical medications as a treatment. Also, clozapine treated patients are examined in some studies, but were not included in others. The rate of clozapine treatment in early-course patients is minimal. Thus, understanding the influences of confounding factors is important. Unresolved issues include whether the factors predicting more adverse neurobiological and functional outcomes include the number of relapses and re-treatments, the duration of the relapses, the intensity of treatment after relapse, or the severity of symptoms during the relapses. However, the evidence is
ACCEPTED MANUSCRIPT 13 clear and consistent that relapse and re-treatment early in the course of illness in schizophrenia is associated with risk for adverse cortical changes.
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A longitudinal study of first episode patients who had received successful
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treatment for a first episode of schizophrenia indicated that the total duration of time spent experiencing psychosis during relapses predicted brain volume loss
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(Andreasen et al., 2013). Interestingly, symptom severity during or between
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relapses did not predict loss of cortical volume and the intensity of treatment, indexed by total antipsychotic exposure during the entire follow-up period, also
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predicted loss of cortical gray matter. These data are among several studies that have shown that, on average, total antipsychotic treatment exposures are correlated
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with cortical volume loss. A systematic review suggested that this effect held up across studies, with several limitations (Fusar-Poli et al., 2013). The most major of
compare:
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these limitations is that the authors of this review were not able to systematically
a. Typical vs. atypical antipsychotic treatment b. Treatment response: responsive vs. resistant c. Treatment adherence. These are clearly major issues. If positive treatment response, meaning less psychosis over time, is associated with less volume loss then the suggestion would be that nonresponsive patients should have their medications reduced or stopped. Nonadherent patients are not exposed to medications because they do not take them regardless of their symptom severity. Thus, if excessive psychosis associated with nonadherence leads to increased medication doses prescribed, the increased
ACCEPTED MANUSCRIPT 14 dose of medication would still have no association with cortical atrophy because there was no real medication exposure. This is a major issue with all studies that
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correlate medication doses that are prescribed with objective outcome variables
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such as cortical changes in the absence of information regarding medication actually taken by the patients.
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Given these interpretive problems, the most critical question to be answered
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is whether positive treatment response and lack of relapses predicts a better course of brain integrity during and across antipsychotic treatments. This question can
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only be answering by comparing patients receiving the same treatment who vary in their overall clinical response and examining differential brain changes in those two
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groups. Neuroimaging studies reviewed below have addressed the possible beneficial effects of clozapine treatment on cortical structure and function, in
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contrast to the potential adverse effects of treatment with higher doses of other medications. However, it is clear from later studies as well as the early CT scan work that persistent symptoms confer risk of cortical changes and that concurrent treatment with conventional medications or atypical antpsychotics other than clozapine at best provides no protection against cortical changes. Some studies of early course patients have provided evidence that those patients who show progressive cortical changes also manifest cognitive deterioration as well. In specific, Ho et al. (2003) reported a correlation between progressive loss of gray matter and worsening in executive functioning. In specific, a 3-year follow-up of first episode patients found variations in changes both white and gray matter across individuals. Those individuals who lost volume in both
ACCEPTED MANUSCRIPT 15 frontal lobe white and gray matter showed evidence of deterioration in their executive functioning. Those who lost only white matter had evidence of increased
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negative symptoms, suggesting different risk factors for the development of
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persistent negative symptoms and everyday disability associated with worsening cognitive performance. Given the prominence of cognitive deficits in treatment
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resistant patients, such cognitive changes may contribute to poor outcomes over
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time. In a study examining first episode patients, Lappin et al. (2013) found that increases in hippocampal volumes after treatment of a first psychotic episode led to
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better cognitive and functional outcomes, suggesting bidirectional effects of volume changes in the CNS during psychosis.
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Multiple neuroimaging studies, reviewed in Nakajima (2015), have compared both healthy controls and treatment responsive patients to TRS patients. They have
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reported both alterations in cortical thickness and volumes as well as connectivity differences between these groups. As described below, imaging has also been used to predict treatment response and to characterize functional brain changes following treatment with clozapine. In addition, several studies using functional imaging have suggested reduced metabolism in the prefrontal cortex and increases in basal ganglia metabolism in TRS patients ( e.g., Molina et al., 1997). Progression of Cortical and Functional Deterioration in Treatment Resistant Patients. There has surprisingly been little research on the course of cortical and functional change in chronic treatment resistant patients. This may be due to funding priorities, where a focus on early intervention and prevention has led to a
ACCEPTED MANUSCRIPT 16 shift in funding away from studying cases with established illness. Partially this situation may be due to ethical and human subjects concerns, where very impaired
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and psychotic patients may not be able to provide informed consent to participate in
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neuroimaging research.
In one of the first imaging studies addressing progressive cortical change in
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treatment resistant patients, Davis et al. (1998) reported that Kraepelinian patients
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manifested left-sided ventricular enlargement compared to treatment responsive patients followed over the same 5-year follow-up period. The most important part
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of this study is that the major differences between the treatment resistant (Kraepelinian) patients and the treatment responsive patients was symptoms alone.
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Both groups were receiving treatment with conventional antipsychotic medications and both had a history of extended prior hospital stays. Total spent in the hospital
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over the lifetime was correlated with the rate of ventricular enlargement in the Kraepelinian patients only.
This study suggested the role of continued psychotic symptoms despite treatment as a risk factor for ventricular changes and, by inference, cortical atrophy. An MRI study of 24 patients with schizophrenia with an average four-year follow-up also reported evidence of decreases in cortical volume in a number of critical brain regions when compared to healthy controls of a similar age (Mathalon et al.,2001) . Broadly consistent with the results of the Davis et al study, averaged severity of psychopathology as well as the proportion of time spent hospitalized in the fouryear follow-up period was correlated with decreases in brain volumes, suggesting
ACCEPTED MANUSCRIPT 17 that “total dose” of psychosis was associated with risk for cortical atrophy. Similar findings were reported by Gur et al. (1998).
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Some more clinically focused studies have examined the predictors of
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cognitive and functional decline in chronic schizophrenia patients with extended hospital stays. In a series of studies of the same large sample of chronically
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hospitalized inpatients, the severity of psychotic symptoms, despite on-going
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antipsychotic treatment, was found to predict the risk for cognitive and functional decline. In the first study (Harvey et al.,1999) severity of psychosis despite
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antipsychotic treatment at baseline predicted risk for cognitive and functional decline over a 36 month period. In a 6-year follow-up in a larger sample (Harvey et
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al., 2003; n=424), the course of cognitive functioning predicted the course of functional disability. Interestingly, and consistent with the results of the earlier,
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shorter study, patients whose psychotic symptoms were stably high or worsened during the follow-up period showed the greatest risk for cognitive decline. The declines seen in these patients did not resemble those seen in a sample of patients with Alzheimer’s disease followed up over the same time period (Friedman et al., 2001). Psychosis despite adequate conventional antipsychotic treatment was associated with cognitive and functional decline over time. Because of the age and baseline levels of impairment in these patients, imaging studies were not possible. Studying patients over the age of 50, Fucetola et al., (2000) reported a specific decline in executive functioning beyond that seen in healthy individuals. Similarly, Granholm et al. (2010) reported reduced performance-related benefits from retesting in older patients with schizophrenia compared to healthy individuals,
ACCEPTED MANUSCRIPT 18 while Bowie et al. (2008) reported that high-load information processing tests were more sensitive to age-related declines than traditional neuropsychological measures
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in a community dwelling older sample. Finally, two follow-up studies of ambulatory
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patients (Harvey et al., 2010; Reichenberg et al., 2014) found that cognitive and functional decline was detected in patients with a history of previous institutional
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stay (generally due to treatment resistance) and was absent in patients who never
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experienced such an extended stay.
Clozapine for treatment resistant schizophrenia. Clozapine has been proven in
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multiple studies to have efficacy for the reduction of psychotic symptoms in patients who have failed repeated treatments with other medications. After the conclusive
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demonstration of the efficacy of the medication in treatment-resistant patients compared to conventional antipsychotic treatments (Kane et al, 1988), clozapine
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treatment was re-introduced to the US. Multiple studies have shown that in truly treatment resistant patients, clozapine is superior to other atypical antipsychotic medications, including those that are chemically quite similar such as olanzapine. In the large-scale CATIE study, clozapine again demonstrated superiority to other medications after prospective confirmation of treatment resistance (McEvoy et al., 2006). Clozapine’s potential side effects include functional bone marrow suppression and agranulocytosis. These risks necessitate leukocyte and neutrophil count monitoring throughout the duration of treatment. Other potential side effects include diabetic ketoacidosis (DKA), gastrointestinal (GI) hypomotility, and myocarditis. Furthermore, Ahmed et al. (2008) demonstrated that almost half of the
ACCEPTED MANUSCRIPT 19 clozapine patients in his study developed metabolic syndrome. Seizure threshold is lowered with clozapine treatment, which is actually a benefit in some situations, as
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we will see in our upcoming discussion of ECT for clozapine nonresponders. There
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are another of additional side effects as well (Miller and Buckley, 2014). Despite the common characterization of clozapine as a medication with a
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substantial side effect burden, as described above, clozapine has been found to be
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the antipsychotic drug treatment associated with the lowest mortality. In a whole nation study, Tiihonen et al. (2009) studied mortality in a cohort of 66,881
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schizophrenia patients in Finland, and found that clozapine demonstrated the lowest all cause mortality of any antipsychotic medications. This phenomenon is
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likely due to suicide risk reduction, which makes several critical points. Suicide is a major problem for patients with schizophrenia and strikes over the entire lifetime
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course. Weight gain and metabolic syndrome develops gradually and can be detected and treated. Suicide is often precipitous and not immediately predictable or preventable. Thus, other than agranulcytosis, which is rare (3%) and generally (but not always) occurs early in the course of treatment, clozapine side effects are only dangerous if unmanaged. Does clozapine prevent or reverse cortical deterioration? The relationship between clozapine treatment in treatment resistant patients and changes brain functioning is an under researched topic, and a few studies have come to conflicting conclusions. These mixed results run the entire range of possible outcomes, including studies that have demonstrated that clozapine treatment generically reduces change, reduces it only in responders, or does not have an effect
ACCEPTED MANUSCRIPT 20 at all. In the van Haren et al. (2007) study relapses in schizophrenia patients were associated with decreases in gray matter density in the left superior frontal area
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(Broadmann areas 9/10), left superior temporal gyrus (Broadmann area 42), right
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caudate nucleus, and right thalamus, patients receiving clozapine treatment showed attenuated effects. In fact, increases in the amount of clozapine administered to
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patients narrowed the difference in superior frontal grey matter density between
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schizophrenic patients and healthy controls. It is worth noting that this affect was associated with clozapine treatment but not treatment with typical antipsychotic
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medication. These results are congruent with a prior study that reported progressive global grey matter loss in patients treated with typical antipsychotics,
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but not atypical antipsychotics (Lieberman et al., 2005). However, this was a study of olanzapine treatment in first episode patients, so the comparisons are not direct.
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Van Haren et al. (2011) showed that higher clozapine doses were associated with less thinning in many frontal areas and the right cingulate. Nonetheless, patients receiving clozapine had more pronounced cortical thinning in the left superior temporal cortex. The small sample sizes in this study for clozapine treated patients may be associated with these apparently inconsistent findings. Molina et al. (2005) found that clozapine treatment was associated with grey matter increases and white matter decreases in the parietal and occipital lobes. The greatest gain of gray matter was seen in the occipital region. They also found that frontal grey matter increased in a group of chronic treatment-resistant patients treated with clozapine. The gain in gray matter was more pronounced in the group treated with clozapine than the previously treatment-naive group treated with
ACCEPTED MANUSCRIPT 21 risperidone. Although this may be due to the greater atrophy at baseline, their results suggest that such atrophy may be reversed with clozapine treatment.
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On the contrary, the results of Ahmed et al. (2015) suggest that clozapine
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treatment is not correlated with arrest or reversal of brain volume loss or cortical thinning. In that investigation, patients with TRS as a group had more cortical
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thinning than HC, particularly in the left medial prefrontal cortex. Patients with the
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least thinning were the most likely to have a positive clinical response to clozapine. But because most patients treated with clozapine in their study improved clinically,
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the loss of grey matter appears associated with an ongoing neurotoxic pathophysiology that is not necessarily associated with the concurrent presence of
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uncontrolled psychotic symptoms. So, in the case of the patients in the Ahmed et al., study, clozapine- associated clinical improvement did not lead to attenuation of
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cortical atrophy during the followup period. These studies reviewed above are naturalistic studies that often have small sample sizes and are limited by the fact that they are post hoc studies. The weight of the evidence suggests that cortical atrophy is associated with uncontrolled psychosis during period of relapse. Arrest of a cortical atrophic process or reversal of previous atrophy with clozapine treatment is a much more inconsistent finding and is based on a much smaller evidence base. What is clear, however, is that relapses have neurotoxic effects that may include causing cognitive and functional decline. Clozapine treatment has not been implicated in causing progressive volume loss in the cortex, such that it appears to be the best treatment strategy for patients who have developed treatment resistance. Whether long-term treatment with
ACCEPTED MANUSCRIPT 22 clozapine has the potential to reverse previous cortical changes is a question for further research.
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Conclusions.
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Persistent psychosis and relapse followed by retreatment have been shown to have both neurobiological and cognitive and behavioral consequences. Treatment
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resistance doubles in its prevalence following the first episode of schizophrenia and
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relapses and re-treatments are extremely common even I responsive cases. Cortical atrophy is clearly demonstrated as a function of psychosis and treatment burden,
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including in cases who manifest treatment resistant schizophrenia. Clozapine is the only treatment with demonstrated efficacy for treatment resistant schizophrenia
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and there are multiple benefits of clozapine treatment in those cases whose response is positive. Clearly the search of other treatments to benefit the 20% of all
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patients with schizophrenia who fail to benefit from all available treatments (“Ultra Resistant Schizophrenia: URS”; Nakajima et al., 2015) is a priority.
ACCEPTED MANUSCRIPT 23 References
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