Research Trail – Schizophrenia Essay


[1] Le Grange, D., O’Connor, M., Hughes, E. K., Macdonald, J., Little, K. & Olsson, C. A. (2014). Development antecedents of abnormal eating attitudes and behaviours in adolescence. Research Trail – Schizophrenia Essay


International journal of eating disorders, 47(7), 813-824
Search engine: iFind research, Psychinfo; Search terms ‘Abnormal behaviour AND psychology’ ‘Eating Disorders’
This study is on developmental data from an Australian population- based birth group to identify developmental markers of abnormal eating habits and behaviours in adolescence. Within this research there were two main aims, the first aim was to develop a model identifying infant and childhood developmental correlation of abnormal eating habits and behaviours in adolescence. The second aim was to explore the potential gender differences. The data for this subject was drawn from a 30 year old longitudinal study that has followed the health and development of a population based group across 15 waves of data collection: The Australian Temperament Project. Participants in this research are the 1,300 youth who completed the 11th survey at the age of 15-16 and who completed the eating disorder inventory. Negative- Due to the participants answering a survey the results could suffer from social desirability bias which could affect the validity of the study. This research is useful as it indicates the gaps in our understanding of the origins of abnormal eating habits and the behaviour in adolescence.Research Trail – Schizophrenia Essay

[2] Young, J. W. & Geyer, M. A. (2015). Developing treatments for cognitive deficits in schizophrenia: the challenge of translation. Journal of psychopharmacology, 29(2), 178-196
Search engine: iFind research, Psychinfo; search terms ‘Schizophrenia AND abnormal behaviour’
This study refers to the treatments established to reduce the effects of schizophrenia, such as antipsychotics.Research Trail – Schizophrenia Essay Their knowledge has been enhanced from researching this subject as they found cognitive enhancers are required for patients in order to improve their everyday lives. Antipsychotics treat psychosis but they do not enhance cognition therefore they are not antischizophrenics. They suggest that the cognitive domains will need to be measured similarly in animals and humans so they can test their targets before conducting expensive clinical experiments. This is useful as it shows how psychology has helped developed the treatment of schizophrenia. It has aided in the development of cognitive therapies to improve patients everyday life.Research Trail – Schizophrenia Essay

[3] Brune, M., Schaub, D., Juckel, G. & Langdon, R. (2011). Social skills and behavioural problems in schizophrenia: The role of mental state attribution, neurocognition and clinical symptomatology. Psychiatry Research, 190(1), 9-17.
Search engine: iFind research, Psychinfo: search terms ‘Schizophrenia AND abnormal behaviour’
This research believes that poor social skills and unusual behaviours are the main features of schizophrenia.Research Trail – Schizophrenia Essay They believe that there is a relationship between poor social skills and the presence of negative social skills, but other symptom domains seem less clear. Therefore to examine the relationship between social skills, neurocognition and clinical symptomatology, the researchers gathered data from previous studies in to one sample of 69 patients with schizophrenia. The sample was arranged for IQ, age range and attention deficits. The results for this study found that the capacity for mental state attributions plays in important role for social skills in schizophrenia. This study proposes a few key suggestions of the symptoms of schizophrenia which allow us to recognise them in the diagnosis of this mental illness, which then allows researchers to form treatments.Research Trail – Schizophrenia Essay
[4] Janes, E., Riby, D. M. & Rodgers, J. (2014). Exploring the prevalence and phenomenology of repetitive behaviours and abnormal sensory processing in children with Williams Syndrome. Journal of Intellectual Disability Research, 58(8), 746-757.
Search engine: iFind research, Psychinfo: search terms ‘Abnormal behaviour AND psychology’ ‘Contribution OR impact OR add OR influence’
The study is a small amount of research with people who have Williams Syndrome mostly young children aged 6-15. The research suggests that children with the condition may be vulnerable to sensory processing abnormalities and usually present repetitive and restricted behaviours.Research Trail – Schizophrenia Essay The study consisted of parents of 21 children with Williams Syndrome who completed a semi-structured interview designed to draw out the form, frequency, impact and developmental course of a range of sensory processing abnormalities and repetitive behaviours. The findings show that the sensory processing difficulties are predominantly characterised by hypersensitivities. Parents reported a wide range of restricted and repetitive behaviours which were often associated with their child’s sensory symptoms. This study contributes to our understanding of the sensory functioning and repetitive behaviours in Williams Syndrome. It also indicates the difficulties experiences by children who have the disorder. Negative- difficult to compare the results of the interviews because each interview is unique.Research Trail – Schizophrenia Essay

Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. Research Trail – Schizophrenia Essay These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia.Research Trail – Schizophrenia Essay This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work). Despite the effort of many experts in the field, however, schizophrenia remains a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan. Comprehensive treatment entails a multi-modal approach, including psychopharmacology, psychosocial interventions, and assistance with housing and financial sustenance. Research to date suggests a network of genetic, neural, behavioral, and environmental factors to be responsible for its development and course. This article aims to summarize and explain recent advancements in research on schizophrenia, to suggest how these recent discoveries may lead to a better understanding and possible further development of effective therapies, and to highlight the paradigm shifts that have taken place in our understanding of the diagnosis, etiopathology, and treatment.Research Trail – Schizophrenia Essay

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Historical background and diagnosis
The concept of schizophrenia as a disease entity has undergone major changes over the past century. Kraepelin distinguished chronic psychoses from functional decline, which he termed dementia praecox, and episodic psychoses, which he called the manic-depressive insanity [1]. Subsequent literature pointed to considerable symptomatic overlap between these disorders, leading to the rather loosely defined, and therefore unreliable, diagnosis of schizoaffective disorder [2]. Over the past century, these categories have—to a large extent—remained the same, as summarized in the current classificatory systems: the DSM and the International Classification of Diseases (ICD) [3].Research Trail – Schizophrenia Essay

A noteworthy recent development in psychiatry was the release of the fifth edition of the DSM in 2013. Although no major changes were made to the definitions of schizophrenia and other psychotic disorders, efforts were made to increase simplicity of diagnoses. First, the Kraepelinian subtyping of schizophrenia into paranoid, disorganized, catatonic, and undifferentiated type was eliminated because of a lack of evidence supporting the validity of these distinctions. Second, catatonia was moved to become a specifier across diagnoses rather than a schizophrenia subtype. Third, a more longitudinal approach to this diagnosis was defined. Finally, the previous emphasis on Schneider’s [4] “first rank” symptoms (i.e. delusions of thought broadcast and thought insertion) and bizarre delusions was eliminated. Although all this improved the ease of use of the criteria, the validity of these boundaries remained largely in question.Research Trail – Schizophrenia Essay

Over the past two decades, it has become increasingly clear that there are neurobiological [5], genetic [6], and treatment response [7] overlaps between these disorders, bringing into question the validity of these categories [8]. A dimensional approach to psychopathology and the view that biological impairments may cut across categories have led to the recent introduction of the research domain criteria (RDoC). RDoC [9] refers to a framework of representing accruing information across molecular, cellular, circuit, and behavioral domains agnostic to symptom-based diagnoses. Although this approach is still in its infancy, it might offer a useful framework for future research that may yield a neuroscience-informed classificatory system [8].Research Trail – Schizophrenia Essay

There has also been interest in defining schizophrenia beyond the symptoms listed in the DSM, with recent consideration of cognitive decline as a core feature with psychosis considered by some as a later development [10, 11]. Along these lines, there have also been significant efforts to better understand and characterize schizophrenia at earlier stages of the illness with the concept of schizophrenia prodome, which became of increasing clinical interest [12]. Schizophrenia prodrome, sometimes referred to as ultra-high-risk state or psychosis risk syndrome, is thought to be a spectrum of attenuated positive and negative symptoms that individuals may display several years to months before converting to schizophrenia.Research Trail – Schizophrenia Essay

Recent research has begun to elucidate risk factors for conversion to psychosis, including early impaired cognitive (e.g. inattention, concentration difficulties) and social functioning [13]. Even though not all risk factors are currently known, approximately 35% of the individuals with prodromal symptoms convert to schizophrenia [14, 15]. The North American Prodromal Longitudinal Study, a large multicenter study, has begun to demonstrate substantive neuroanatomical [16], neurophysiological [17], neurocognitive [18], and neurohormonal [19] changes during the prodromal phase that may contribute to the risk of schizophrenia [20].Research Trail – Schizophrenia Essay

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Pathophysiology and etiology
Schizophrenia has a substantial genetic component, with a high heritability (up to 80%), indicating that about 80% of the variation in the trait of schizophrenia may be attributed to genetic factors [21]. Genome-wide association studies (GWASs), which compare the genomes of thousands of healthy and affected individuals, have found several genes associated with increased risk of developing schizophrenia, such as NRGN and ZNF804A [22, 23]. Recent research suggests that genetic risk for schizophrenia is composed of many common genetic alterations, each with a small effect, along with a few uncommon genetic alterations with a larger impact [24]. Additionally, genes that confer risk for schizophrenia may also be associated with bipolar disorder and other psychiatric disorders [25] (Figure 1).Research Trail – Schizophrenia Essay

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Figure 1.
Etiology of schizophrenia
The multifactorial etiology of schizophrenia including a) rare genes that have a large effect, b) common genes that have a small effect, and c) the environmental factors and gene-environmental interactions that confer risk for schizophrenia.Research Trail – Schizophrenia Essay

Various environmental factors may interact with susceptibility genes to increase the risk of schizophrenia; these interactions are the focus of an emerging area of investigation called epigenetics. One of the few replicated findings in this relatively new field is an interaction between cannabis use and the AKT1 gene on the risk of psychosis [26, 27]. Other findings in epigenetics that have not yet been replicated include interactions between a history of fetal hypoxia and hypoxia-related genes on volume of the hippocampus [28] and interactions between childhood trauma and variants of the serotonin transporter [29] and COMT gene [27] on cognitive functioning. Although epigenetics research has the potential to greatly impact clinical practice, few studies have attempted to replicate findings. Among those studies attempting replication, few have been able to confirm previous findings, implying possible publication bias and a need for larger sample sizes in this type of research [30].Research Trail – Schizophrenia Essay

Although early neurobiological theories of schizophrenia largely focused on excessive dopamine, more recent research reflects a more nuanced role of dopamine and has pointed to the importance of other neurotransmitters such as GABA and glutamate. Recent animal models [31] and genetic studies of humans [32] suggest that hypofunction of the N-methyl-D-aspartate (NMDA) glutamatergic receptor may underlie schizophrenia. Glutamate models of schizophrenia may provide an additional explanation to the dopaminergic models for the cognitive symptoms of this illness and may ultimately yield novel pharmacological treatment approaches [33].Research Trail – Schizophrenia Essay

Neuropathology research indicates that schizophrenia is characterized by abnormal maturation of prefrontal networks during late adolescence and early adulthood, likely due to excessive pruning of synapses and dendritic spines [34, 35]. Pre- and post-synaptic abnormalities in inhibitory neurons such as the parvalbumin interneuron may disturb these critical neurodevelopmental processes [36]. Recent research using optogenetics indicates that parvalbumin interneurons may influence gamma oscillations, which in turn are associated with cognitive function [37]. Myelination (another critical neurodevelopmental process) is also abnormal in schizophrenia, as shown by post-mortem studies demonstrating reduced expression of myelin basic protein in cortical regions [38]. Disturbances in both myelination and the inhibitory control of synaptic pruning may contribute to cognitive deficits in schizophrenia [39]. These recent advances in neuropathology build upon previous post-mortem research demonstrating reduced neuropil, but not a reduced number of neurons, in the brains of adults with schizophrenia [40].Research Trail – Schizophrenia Essay

Recent studies have shown compelling evidence that neuropathological changes in schizophrenia might set in during the critical period of adolescence, proximal to the onset of psychosis. Gray-matter declines appear to occur in the early phase of schizophrenia and may be related to poorer outcomes. The early phase of psychosis may also be associated with elevations in presynaptic dopamine turnover [41] as well as increases in glutamatergic activity [42]. These observations highlight the importance of early recognition and intervention targeted to the pathophysiological processes close to the onset of psychosis.Research Trail – Schizophrenia Essay

In the past several years, inflammation and oxidative stress have re-emerged as potentially important aspects of pathophysiology in a subset of affected individuals. Multiple studies have demonstrated elevated levels of cytokines and other signs of immune system activation in individuals with psychosis [43, 44], and genetic studies have reported correlations between schizophrenia and genes involved in the immune response [23]. Recent rodent work has observed that exposure to infectious or inflammatory agents in utero can lead to behavioral and neurobiological alterations resembling those seen in schizophrenia [45]. Oxidative stress, which is associated with inflammation, may also be elevated in schizophrenia. For example, a recent meta-analysis of studies on oxidative stress markers observed reduced levels of the anti-oxidant red blood cell superoxide dismutase in schizophrenia [46].Research Trail – Schizophrenia Essay

Additionally, some recent work has focused on autoimmune dysfunction as a cause of psychosis. For example, anti-NMDA-receptor encephalitis is a potentially treatable but under-diagnosed cause of psychosis that results from the production of antibodies against NMDA receptors [47]. A number of young individuals presenting with their first episode of psychosis may have detectable auto-antibodies against this receptor or other neuronal proteins, such as voltage-gated potassium channels [48]. In addition, epidemiological data suggest a bi-directional association between psychosis and some common autoimmune diseases: individuals with one type of illness are at greater risk of developing the other type [49]. The potential therapeutic applications of these findings are being actively explored.Research Trail – Schizophrenia Essay

Various forms of imaging research have been critical in advancing our understanding of the neurobiology of schizophrenia. Studies have reported subtle structural alterations, including enlargement of the third and lateral ventricles, slight reductions in whole-brain gray matter volume, and slight reductions in the volumes of temporal, frontal, and limbic regions [50, 51]. Functional imaging studies have observed reduced activation of the dorsolateral prefrontal cortex during tasks of executive function [52] and abnormalities of limbic system activation during tasks involving emotional stimuli [53]. In addition, studies using diffusion tensor imaging, a method of visualizing white matter, have found evidence of white matter changes in frontal and temporal lobes that would imply decreased connectivity among these regions [54]. Together, these findings support the conceptualization of schizophrenia as a disorder of brain connectivity [55]. Studies in the past few years have used various forms of network analysis to uncover decreased regional connectivity in both first-episode schizophrenia [56] and the broader psychotic spectrum.Research Trail – Schizophrenia Essay

The next major challenge is to translate neuroimaging findings into the clinical setting. Consequently, recent research has started to integrate various imaging modalities with genetic, electrophysiological, and clinical data to identify biomarkers, which may eventually be relevant for clinical diagnosis and management.

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Pharmacological treatments in schizophrenia
Antipsychotic drugs have been the mainstay of schizophrenia treatment since the introduction of chlorpromazine, focusing on decreasing the frequency and severity of psychotic episodes as well as improving the functional capacity of individuals with schizophrenia [57]. However, adverse effects and suboptimal outcomes associated with first-generation antipsychotics (FGAs) led to the development of second-generation antipsychotics (SGAs), which due to their 5HT-2A antagonism are generally associated with reduced extrapyramidal symptoms (EPSs) as compared with FGAs [58]. However, there is controversy concerning the categorization of FGA and SGAs; some literature differentiates them based on their ability to cause EPSs, whereas other studies base it on their antagonism of the dopamine D-2 receptors [59, 60]. The first and most efficacious SGA for the treatment of refractory schizophrenia, clozapine, is limited by the risk of agranulocytosis, which necessitates the use of periodic monitoring of blood cell counts. EPSs are lowest with clozapine and highest with haloperidol. All drugs except haloperidol, ziprasidone, and lurasidone produce more weight gain, with olanzapine and clozapine producing the greatest weight gain. Prolactin elevation is highest with risperidone and paliperidone. All drugs, except for amisulpride, paliperidone, sertindole, and iloperidone, are significantly more sedating than placebo [61].Research Trail – Schizophrenia Essay

Several large-scale investigations suggest no clear superiority of SGAs over FGAs among first-episode patients [62] or chronic patients [63] in regard to positive, cognitive or social outcomes [64]. Furthermore, both FGAs and SGAs do not sufficiently target negative symptoms (with only olanzapine and asenapine showing moderate effects [65-67]) and sometimes insufficiently treat positive symptoms [68, 69]. Clozapine seems to be the most effective medicine, whereas the effectiveness of olanzapine and risperidone over other antipsychotics remains controversial [61, 70-72]. In terms of relapse prevention, SGAs have a modest benefit compared with FGAs [73]. Newer antipsychotics such as asenapine, iloperidone, lurasidone, and paliperidone do not seem to be significantly better than haloperidol [61], and for the treatment of refractory schizophrenia, clozapine has been shown to be significantly more efficacious than other agents [74-78]. However, several studies suggest that olanzapine and risperidone have greater efficacy over other antipsychotics, but this remains controversial and more research is necessary in this area. Additionally, amisulpride, olanzapine, clozapine, paliperidone, and risperidone show significantly lower all-cause discontinuation than several other agents [61, 79-81]. The Schizophrenia Patient Outcome Research Team (PORT) summarized strong empirical support for both FGAs and SGAs in acute and maintenance treatment of schizophrenia and for the use of clozapine for treatment-resistant positive symptoms, hostility, and suicidal behaviors [82].Research Trail – Schizophrenia Essay

Research over the past decade further investigated agents that stimulate the NMDA glutamate receptor, including partial and full agonists at the glycine site and glutamate 2/3 receptor agonists, and found that they may ameliorate negative symptoms with some success if used in conjunction with antipsychotics [83]. The PORT concludes, however, that there is still limited information on the use of adjunctive pharmacological agents as well as the treatment of co-occurring substance abuse [82]. None of the pharmacological agents to date effectively ameliorate cognitive deficits, which are a core feature of schizophrenia; larger and more rigorous studies are needed to examine the potential pro-cognitive effects of medications that impact dopaminergic, nicotinergic, glutamatergic, GABAergic, and other novel targets [84].Research Trail – Schizophrenia Essay

Long-acting injectable antipsychotics are helpful in treating patients with poor medication adherence and have more controlled distributions in the body; for these reasons, they are superior to oral antipsychotics in preventing hospitalizations [85] and may foster a better therapeutic alliance. Both FGA (haloperidol and fluphenazine) and SGA (risperidone, paliperidone, olanzapine, and aripiprazole) medications are now available as long-acting preparations. Recent preliminary investigations suggest a therapeutically beneficial response to dose reduction and alternate day dosing [86] in the early stages of remitted first-episode psychosis. However, more research is needed to confirm these observations [87].Research Trail – Schizophrenia Essay

Recent advances in the understanding of schizophrenia have restored interest in inflammatory and oxidative stress pathways as the pathogenesis for a subset of patients. Research on human and animal models supports this new insight [88-93]. In a review by Sommer et al., 26 double-blind randomized controlled trials reported on the efficacy of anti-inflammatory agents such as aspirin, celecoxib, davunetide, fatty acids (eicosapentaenoic acids and docosahexaenoic acids), estrogens, minocycline, and antioxidants such as N-acetylcysteine (NAC) as treatment augmentation for schizophrenia [94]. Aspirin, estrogens, and NAC showed significant effects; in contrast, celecoxib, minocycline, davunetide, and fatty acids showed no significant difference [95]. Whereas more research is needed to investigate the therapeutic effects of both current and novel anti-inflammatory agents, current evidence does suggest a benefit in treating inflammation.Research Trail – Schizophrenia Essay

Pharmacogenomics is a growing field in the treatment of schizophrenia and can bring the field of psychiatry closer to achieving evidence-based personalized medicine with the goals of predicting better treatment response and reducing medication-induced side effects. For example, polymorphisms in the serotonergic system are associated with the efficacy of clozapine and risperidone, dopamine D3 receptor polymorphisms are associated with response to clozapine and olanzapine, and D2 variants are associated with the efficacy of risperidone [96]. As for side effects, the serotonergic system (HTR2C) and hypothalamic leptin-melanocortin genes (MC4R) can predict antipsychotic-induced weight gain [97, 98], cytochrome P450 (CYP2D6) and dopamine receptor variants are associated with tardive dyskinesia [96, 99], and major histocompatibility complex (human leukocyte antigen [HLA]) markers have been consistently found to be associated with clozapine-induced agranulocytosis. However, despite progress made in pharmacogenomics, the field has encountered obstacles such as replication inconsistencies, small study sizes, and lack of randomized control trials.Research Trail – Schizophrenia Essay

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Psychosocial treatments
Antipsychotic medications are a necessary but not sufficient treatment for schizophrenia. The broad objectives of treatment should be reducing the frequency and severity of episodes of psychotic exacerbation as well as improving the functional capacity and quality of lives of the individuals afflicted with the illness. Thus, in tandem with research over the past decades, the urgently needed multimodal care has continued to evolve. Psychoanalytic treatments beginning in the early 20th century seemed to insufficiently address the burden caused by the illness. In the early ’60s, major role therapy and family psychoeducation were introduced based on the interpersonal and family theories of psychosis. With further research in the field and increased knowledge about the nature of the specific deficits (cognitive, social, and affective), more disease-specific psychotherapies started to develop in the ’80s and ’90s. These therapies target both pathophysiology and other core manifestations of the disease.Research Trail – Schizophrenia Essay

The PORT recently provided an extensive summary of the current evidence-based psychosocial treatment [100]. Cognitive behavioral therapy (CBT) is based on the theory that the way we interpret events has cognitive, emotional, and behavioral consequences, which lead to the creation and maintenance of unhelpful responses. CBT has been a successful approach for other mental illnesses such as depression [101] and anxiety [102]. More recently, CBT has been applied to the treatment of positive as well as negative symptoms. Research shows that CBT can improve positive symptoms [103, 104] but is less consistent with the improvement of negative symptoms [105, 106]. A recent review shows that CBT may mostly be efficient in the short term (i.e. more than 12 months) [107].Research Trail – Schizophrenia Essay

Social skills training (SST) is based on a behavioral model that targets the improvement of a person’s ability to function skillfully in social situations (i.e. interactions). SST has emerged among the possible treatments for schizophrenia [108] to address social skill deficits primary to developmental derailments but also secondary due to both positive and negative symptoms [109]. SST has been found to improve both positive and negative symptoms [106], and some of the improvements may persist at follow-up [110].Research Trail – Schizophrenia Essay

Family therapy is based on a model that suggests that problematic behaviors are maintained and created by patterns in systems (i.e. proximal or distal family) [111]. System theory underlies the multifamily treatment approach that includes coping recommendations, problem solving, crisis intervention, reduction of pathogenic interactions such as high “expressed emotions” (e.g. criticism, hostility), and (in its core) psychoeducation. Psychoeducation enables not only the patient but also the family and others to recognize early warning signs, which is particularly important in an illness that shows such high vulnerability to stress.Research Trail – Schizophrenia Essay

Assertive community treatment (ACT) offers a multidisciplinary approach that is usually combined with SST, CBT, or any personal support. Teams include peer support specialists and practitioners with expertise in psychiatry, substance abuse treatment, and employment. Although ACT reduces time in the hospital for mental illnesses in general [112], it seems specifically to improve housing stability [113] and reduce hospitalization rates, especially in patients with higher baseline hospitalization rates [113].Research Trail – Schizophrenia Essay

Personal therapy was developed by Hogarty et al. [114] on the basis of supportive psychotherapy. It is one of the few approaches that was designed specifically for people suffering from schizophrenia and combines SST with some common elements of CBT. Personal therapy is modeled to the phases of recovery; thus, it is a long-term endeavor and seems to decrease the probability of relapse [115].Research Trail – Schizophrenia Essay

Cognitive remediation therapy (CRT) is a computer-based intervention that was originally designed to improve deficient cognitive abilities (e.g. attention, memory, and executive function) in people with traumatic brain injury [116] but since has proven to help in people with depression [117], eating disorders [118], and schizophrenia [117]. Whereas CRT by itself has no effect on improving negative symptoms [119], the combination of CRT with SST, groups, and problem solving has been found to be promising [120]. Although preliminary results showed improvements in speed of processing, attention, working memory, executive function, and social cognition in a cognitive enhancement therapy (CET) compared with a personal therapy group, rigorous validation is needed, and the durability of these improvements remains to be investigated.Research Trail – Schizophrenia Essay

For many patients the ability to resume work or school is the ultimate goal. Thus, supported employment interventions are of significant importance – the most commonly studied being the Individual Placement and Support (IPS) [121] model. An important principle of the IPS model is that minimal pre-vocational training is provided, and the job itself becomes the primary training environment. There is clear evidence that supported employment strategies help return people with schizophrenia to work [122], even for young people with their first episode of psychosis [123]. A recent meta-analysis of a total of 11 studies found that competitive employment rates were 61% for patients and 23% for controls and that about 30% out of the 61% worked more than 20 hours weekly. Supported employment further increased the duration of employment (47% of the 52-week year) and the time of onset of employment (approximately 10 weeks earlier than controls). In conclusion, the effect sizes support the effectiveness of evidence-based supported employment as one of the most robust interventions.Research Trail – Schizophrenia Essay

Given the clinical heterogeneity of schizophrenia, it is important to choose the right treatment for the right patient; thus, although supportive treatment might benefit all symptom domains, CBT may be particularly beneficial for those with residual psychotic symptoms and cognitive remediation, SST for those with cognitive or social cognition deficits or both, and ACT for those at risk for frequent hospitalizations or those who have had recent homelessness. There is increasing emphasis on tailoring psychotherapeutic interventions to the phase of the illness (e.g. personal therapy), since the primary goals of intervention might vary across phases. More research is needed, however, to examine active ingredients of the therapeutic modalities that work and to identify the synergistic effects of combinations of interventions that are hypothesis-driven and cost-effective.Research Trail – Schizophrenia Essay

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Conclusions and Future directions
In summary, although our understanding of the causes and treatments of schizophrenia remains limited, several important paradigm shifts have occurred. The diagnosis of schizophrenia is still symptom-based, but increasing amounts of data point to the large genetic and neurobiological overlaps between psychotic, affective, and developmental disorders, suggesting that future classifications of these illnesses need to move toward more evidence-based, valid, and biologically based categories and dimensions. Pathophysiology is now seen as developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions setting in around adolescence. Etiology is now seen as an interaction between multiple genes of small-effect and some rare large-effect genes and unknown environmental factors.Research Trail – Schizophrenia Essay These observations may help therapeutic interventions move beyond the current sole focus on dopamine toward novel therapeutic targets such as glutamate, GABA, and calcium channels. The focus of intervention has expanded beyond relief of psychotic symptoms alone toward restoring functionality by targeting dimensions such as cognitive deficits and negative symptoms. Research is intensifying on the possible utility of several evidence-based psychotherapy modalities in combination with pharmacological approaches. Treatments are still based on serendipitous discoveries from decades ago, and the urgent need is to discover novel interventions based on etiopathology. Finally, recent incremental advances in understanding the etiopathology have motivated vigorous prevention approaches in early phases of the illness and early interventions with novel pharmacological targets and plasticity-based treatments such as cognitive remediation.Research Trail – Schizophrenia Essay

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We would like to thank all the patients that allow us to learn from them, all the collaborators who are doing terrific clinical work, and all the researchers who help us gain better insight.Research Trail – Schizophrenia Essay

Schizophrenia Research: Cognition will serve an important function – a place where interests converge and investigators can learn about the recent developments in this area. This new journal will provide rapid dissemination of information to people who will make good use of it. In this initial article, we comment globally on the study of cognition in schizophrenia: how we got here, where we are, and where we are going. The goal of this first article is to place the study of cognition in schizophrenia within a historical and scientific context. In a field as richly textured as ours it is impossible to hit all the important areas, and we hope the reader will forgive our omissions. Phrased in cognitive terms, our limited presentation of the past is a matter of selective memory, the present is a matter of selective attention, and the future is a matter of selective prospection. This broad introduction emphasizes that cognition in schizophrenia provides clues to pathophysiology, treatment, and outcome. In fact, the study of cognitive impairment in schizophrenia has become wholly intertwined with the study of schizophrenia itself.Research Trail – Schizophrenia Essay

Keywords: Cognition, Schizophrenia, History
Here at last – a journal dedicated to the topic of cognition in schizophrenia: Schizophrenia Research: Cognition. The launch of this journal raises several questions. First: What took so long? Cognition in schizophrenia has been a major focus for a very long time. Exactly how long is somewhat arguable – as seen in the next section, 20, 50, or 100 years are all acceptable answers. From this long-term historical context, it is surprising that it took until 2014 for a publisher to launch a journal focused on cognition in schizophrenia. On the other hand, one could ask provocatively: why do we even need a journal dedicated to this topic? While everyone now agrees that cognition in schizophrenia is an important topic, it is so important that it pervades a wide range of topics. A perusal of schizophrenia-focused journals such as Schizophrenia Bulletin and Schizophrenia Research shows that cognition is a feature of many articles, even those that are not specifically about cognition, including clinical trials, genetics, outcome, and neuroscience.Research Trail – Schizophrenia Essay

Schizophrenia Research: Cognition is expected to serve an important function as an international niche journal – a place where interests converge and investigators gather well-packaged information. It is also intended to take scientific risks. Considering that the journal is open access and will have a fast turn-around, this journal will be a place for rapid dissemination of information to people who will make the most of it. Appropriately for this inaugural issue, the two authors of this paper have been asked to comment on how we got here, where we are, and where are we going. That is, the goal of this first article is to place the study of cognition in schizophrenia within a historical and scientific context. Of course, when the questions are this broad, the answers are not straight forward. Where we came from is a matter of perspective, and we really do not know where we are going with any degree of confidence. But we can make some good guesses.Research Trail – Schizophrenia Essay

We begin with a discussion of the past, fully realizing that some readers (especially younger ones) will be tempted to skip over any section that looks overly retro or sentimental. However, the history of cognition research in schizophrenia is not separable from the history of schizophrenia itself.Research Trail – Schizophrenia Essay

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1. Where we came from
The history of cognition research in schizophrenia can be roughly carved up into 3 eras: the early clinical observations that occurred in the beginning of the 1900s, the assessment-based approaches that emerged after World War II, and the more recent era (roughly the last 20 years) in which cognition research merged into other disciplines. In many ways the three eras are quite distinct in their emphases and their methods, and all reflect their contemporaneous scientific contexts.Research Trail – Schizophrenia Essay

1.1. Clinical observations and formulations in the early 20th century
Until recently, most psychology majors in college were required to take a course on the history of psychology (usually called “History and Systems”). In such a course, students learned historical facts about psychology, one which is that William Wundt is credited with founding the world’s first psychology laboratory in Leipzig, Germany in 1879. Wundt had a long career and trained many students who served as emissaries and conveyed the principles of experimental psychology far and wide. One of his disciples was Emil Kraepelin, who maintained a lifelong interest in psychological phenomena and its applications to psychiatric disorders. It is Kraepelin’s distinction between schizophrenia (dementia praecox) and bipolar disorder that continues to be reflected in the key diagnostic systems (Diagnosis and Statistical Manual, DSM; International Classification of Diseases, ICD) up to the present time. His tendency to label, separate, and divide was not limited to psychiatric disorders; he also noted attentional processing abnormalities in schizophrenia and divided them into two types (Kraepelin, 1971; Nuechterlein and Dawson, 1984). One was a disorder in active attention (aufmerksamkeit) in which patients “lose both inclination and ability on their own initiative to keep their attention fixed for any length of time” (pp. 5–6). The second was an abnormality in passive attention (auffassung) in which there was an “irresistible attraction to casual external impression” (pp. 6–7). In modern parlance, we might call active attention vigilance, and passive attention distractibility. The key point is that his efforts to classify did not stop at diagnoses, but also included efforts to parse cognition.Research Trail – Schizophrenia Essay

If Kraepelin was astute and systematic, Eugen Bleuler was downright prescient. Aside from giving schizophrenia its mysterious (and frequently confusing) name, Bleuler understood at an intuitive level that cognitive impairment was a core part of the illness (Bleuler, 1950). He started by making an important distinction between two types of symptoms: fundamental and accessory. Fundamental symptoms are essentially cognitive in nature. They were separated into simple fundamental symptoms, including problems in association, affectivity, and ambivalence. These simple fundamental symptoms combined to form compound fundamental symptoms, including disturbances in attention. Attention for Bleuler was rather allencompassing. It included some features that we would call vigilance, but also expanded into areas that we might call social withdrawal: “it is evident that the uninterested or autistically encapsulated patients pay very little attention to the outer world” (p. 68).Research Trail – Schizophrenia Essay

In contrast to fundamental symptoms, accessory symptoms were derived from fundamental symptoms and they constitute what we would now call the positive symptoms of schizophrenia: hallucinations, delusions, and behavioral and speech abnormalities. He went on to say that the fundamental symptoms do not necessarily lead to being hospitalized. Instead “it is primarily the accessory phenomena which make his retention at home impossible, or it is they which make the psychosis manifest and give occasion to require psychiatric help” (p. 94).Research Trail – Schizophrenia Essay

Bleuler made many conceptual contributions, but perhaps most relevant to this discussion is his view that psychotic symptoms were secondary to fundamental symptoms, including attentional problems. His hierarchy of symptoms is counter-intuitive, and unfortunately would soon be forgotten. He specifically proposed that the features of illness that were most dramatic, and that necessitated treatment, were somewhat removed from the disease process. He even went on to say that their manifestation was arbitrary: “almost the totality of the heretofore described symptomatology of dementia praecox is a secondary, in a certain sense, an accidental one” (p. 349). Along these lines he proposed that the fundamental symptoms were stable over time, whereas the accessory symptoms waxed and waned.Research Trail – Schizophrenia Essay

In the brilliant, ground-breaking, works of Kraepelin and Bleuler we see the conceptual building blocks of modern studies of cognition. If scientific history was linear and progressive, the field would have moved right along to examine the implications of these insights into the cognition of schizophrenia – but that did not happen. A few notable thinkers (e.g., K. Goldstein, N. Cameron) continued to focus on psychological/cognitive phenomenon in schizophrenia with difficult-to-define concepts such as “abstraction” and “over-inclusive thinking” but it was a niche interest (Bolles and Goldstein, 1938; Cameron, 1939). Instead, much of the focus shifted to the more noticeable and more dramatic “accessory” psychotic symptoms and the importance of cognition was largely forgotten, temporarily.Research Trail – Schizophrenia Essay

1.2. Competing approaches to cognition 1950 – 1980
The post-World War II era was characterized by two distinct, highly empirical, views of the cognitive problems in schizophrenia.

One view was shaped by experimental psychology and it tried to characterize and understand schizophrenia in terms of basic psychological phenomenon (shades of Wundt). This approach is probably best represented by the famous Biometrics Research Unit at the New York State Psychiatric Institute at Columbia University, which was founded by Joseph Zubin in 1954 (Zubin, 1950; Zubin and Spring, 1977). (No less than 3 organizations bestow awards named after Joseph Zubin.) The scientific approach that Zubin and others from the Biometrics program defined was experimental psychopathology and it sought a theoretical understanding of the etiology of schizophrenia.Research Trail – Schizophrenia Essay Their approach to schizophrenia emphasized objective measurement and strong experimental methodology. It also relied on the assumption that the most fruitful way to study the etiology of psychiatric disorders lies in integrative frameworks that use multiple levels of analysis simultaneously (i.e., genetic, biological and psychosocial). This integrative approach is taken for granted now, but was remarkable in the 1960s when it was proposed. As an example of this integrative approach, Zubin, Samuel Sutton, and others examined event related potentials (ERPs) in combination with cognitive tasks (Sutton et al., 1965). This led to a long-standing productive examination of ERP abnormalities in schizophrenia, including the P300, a waveform that is used to reflect allocation of attentional processes.Research Trail – Schizophrenia Essay

To better decompose psychological processes, a substantial amount of effort during this era was devoted to understanding very simple performance-based tasks, such as reaction time (Nuechterlein and Dawson, 1984). Indeed, reaction time was described as the “closest thing to a north star of schizophrenia research” (Cancro et al., 1971). Many studies examined cued reaction time tests in which subjects received trials with regular and irregular intervals between a warning signal (instructing the subject to get ready) and the imperative stimulus (instructing the subject to respond).Research Trail – Schizophrenia Essay David Shakow and colleagues noticed that, unlike controls, patients were unable to benefit from temporal regularity of the intervals (called a set index) once they exceeded a few seconds (Rodnick and Shakow, 1940; Shakow, 1962). Surprisingly, at the longer intervals, the patients were faster for the irregular versus regular trials, a pattern called the cross-over effect. This pattern of performance was perplexing and it never received a clear explanation (aside from largely descriptive explanations of failure to maintain set), but it occupied a prominent role in experimental research, partly because it was unexpected and wonderfully measurable.Research Trail – Schizophrenia Essay

This line of highly empirical research set the stage for clinical psy-chopathology researchers who unabashedly borrowed from experimental psychology, a practice that is commonplace now. This type of translational research took many forms, including borrowing from models of attention, perception, sensory gating, or emotional reactions (Braff, 1993; Green et al., 2011a; Kring and Neale, 1996; Nuechterlein and Dawson, 1984; Nuechterlein et al., 1994). The goal was to closely measure deficits in schizophrenia in precise experimental paradigms, and then infer what the results mean about underlying deficits in the disorder based on existing experimental models. By using normal cognition models as the framework, the results in patients may implicate one visual process or one type of attentional abnormality more than another.Research Trail – Schizophrenia Essay

A distinctly different slant on cognition in schizophrenia was taking hold at the same time as the experimental psychology/psychopathology approach. Although similarly measurement focused, this other approach had its roots in clinical neuropsychology. Human clinical neuropsychology emerged in the post war era, fortified by numerous illustrative case studies of focal lesions from combat injuries (Luria, 1980). In this context, it is not surprising that a cottage industry of studies emerged that compared schizophrenia to neurological patients on standardized clinical neuropsychological assessments. These types of comparisons were in keeping with the common referral questions for psychiatric patients, which were for the purpose of differential diagnosis. Typically the neuropsychologist was asked to determine whether cognitive impairments in a patient were “organic” meaning neurological versus “functional” meaning not neurological. This type of question sounds jarring from a modern viewpoint – it assumes that cognitive deficits are not a core part of schizophrenia, that cognitive deficits for psychiatric patients are not brain-based, and that this distinction between organic and functional is both meaningful and informative. The demise of the word “organic” in the research literature reflects a fundamental shift in assumptions.Research Trail – Schizophrenia Essay

Beyond the conceptual problems, the endeavor to distinguish two types of cognitive impairment was largely futile. After a very large number of studies, the inescapable conclusion was neuropsychological tests could not distinguish cognitive impairments that accompany schizophrenia from those that accompany head injury (Goldstein, 1986; Heaton et al., 1978). In retrospect, it is an unsurprising conclusion and the efforts to discriminate schizophrenia from head injury reflect a time-limited zeitgeist. Although problems in differential diagnosis could be attributed to the tests themselves, the problem in this line of research was the conceptual framing and the stated goals, not the assessment methods. The measures for the most part were reliable and would have been informative for different types of research questions, such as those considered in the next section.Research Trail – Schizophrenia Essay

Neither of these approaches paid much attention to clinical symptoms. We can speculate about the reasons for the omission. First is that the people conducting the studies were mainly clinical and experimental psychologists and not directly involved in treating schizophrenia. Second is that the overlap between cognition and psychotic symptoms tend to be rather modest (Gold, 2004; O’Leary et al., 2000). Third is that, at least for the experimental psychology approach, the emphasis was on cognitive vulnerability factors that would be relatively impervious to changes in clinical state (reminiscent of Bleuler). Fourth is that there was not much effort to parse different types of clinical symptoms until the re-focusing on negative and disorganized symptoms in the 1980s (Andreasen and Olsen, 1982; Crow, 1980). Although cognition and clinical symptoms can safely be considered different domains of schizophrenia, we learned later that there is value in considering areas of shared variance, such as negative and disorganized symptoms.Research Trail – Schizophrenia Essay

1.3. Ramping up to the present: 1980s and 1990s
It is impossible to adequately summarize the ferment and the excitement that characterized the research in cognition in schizophrenia during the latter part of the 20th century. In a selective review such as this one, many key findings and research directions unfortunately will be omitted. For the purposes of illustration, we have selected 3 themes that took root in this period and will also be discussed in terms of current research.Research Trail – Schizophrenia Essay

1.3.1. Cognition and neuroscience
Nothing makes a point quite like a picture of the brain. And what made a very big impression were the initial pictures of the brains of people with schizophrenia (Johnstone et al., 1976; Weinberger et al., 1979). Their brains simply looked different – for example the ventricles appeared to be larger in schizophrenia (Raz and Raz, 1990; Weinberger et al., 1979). The larger ventricles reflected the relative reduction of brain tissue to cerebral spinal fluid. Further, the brain changes were often associated with cognitive impairment, thereby giving cognitive deficits firm neural footing. Consider how the world view for cognition in schizophrenia changed with these neuroimaging applications. Only a few years previously, investigators were administering tests to separate the organic from functional origins of impairment. Suddenly it was obvious that many schizophrenia patients have brains that are not entirely normal and these give rise to cognitive problems. Nonetheless, the inferences were limited from these early studies: for one, the ratio of ventricle to brain is entirely non-specific regarding the affected brain regions, as well as diagnosis. Also the spatial resolution of these imaging techniques (computerized tomography) was very limited compared with later methods.Research Trail – Schizophrenia Essay

The early structural findings were soon followed by functional neuroimaging studies. Initially these were studies of positron emission tomography (PET) in schizophrenia (Berman et al., 1986; Weinberger et al., 1986). Similar to the effects of the early structural imaging, the functional neuroimaging studies forced a reconsideration of brains in schizophrenia. Not only did the brains look different from healthy brains, they functioned differently as well. A common observation was that schizophrenia patients did not activate their frontal lobes as much, and as reliably, as control samples (i.e. hypofrontality) (Andreasen et al., 1992; Buchsbaum et al., 1992; Gur and Pearlson, 1993). Much like the findings of enlarged ventricles, hypofrontality was wholly non-specific for diagnosis (other disorders also showed it), and for mechanisms (there are too many different ways to have reduced frontal activity). Also, functional magnetic resonance imaging (fMRI) would soon replace PET for cognitive activation studies in schizophrenia, although PET is still the method of choice for other types of studies, such as those assessing drug receptor occupancy. The variety of neuroscientific methods used currently to study schizophrenia is huge, and ranges from molecular neurobiology to genomics, to a focus on systems and networks. But this research direction was launched with the early neuroimaging studies and the striking realization that the brain in schizophrenia (as well as its cognitive processes) is available for rigorous study – just as it is in any other brain-based disorder.Research Trail – Schizophrenia Essay

1.3.2. Cognition and outcome in schizophrenia
The introduction of antipsychotic medications in the 1950s carried great promise and high expectations. Some of that promise was realized: the antipsychotic medications did indeed reduce psychotic symptoms in the majority of patients with schizophrenia (Braslow, 1997). It was natural to expect that psychotic symptom reduction would be accompanied by functional improvements and community integration. But that did not happen – in fact, the introduction of these powerful medications made rather little difference for community integration (Hegarty et al., 1994; Jaaskelainen et al., 2013). The reasons were elusive: if the clinical psychotic symptoms were not holding patients back from community reentry, then what was? This puzzle highlighted the difference between remission, meaning the reduction of symptoms, versus recovery, meaning full community participation.Research Trail – Schizophrenia Essay

We know from numerous studies that cognitive impairment is an important correlate and determinant of functioning in schizophrenia (Green, 1996; Green et al., 2000, 2004). Though perhaps not intuitive, cognition is a much better correlate of outcome than psychotic symptoms. We also know that antipsychotic medications have minimal effects on cognition (Keefe et al., 2007a,b). Herein lies the explanation for the discrepancy – antipsychotic medications treat psychotic symptoms, but not cognition. Cognition is related to outcome, but psychotic symptoms are not consistently related. That is why the introduction of antipsychotic medications changed the level of symptomatology for inpatient units, but did little for overall recovery rates.Research Trail – Schizophrenia Essay

This association between cognition and outcome is robust – it was replicated and extended in many in countries, using many different types of assessments, in different patient groups across phase of illness, including prodromal (Carrion et al., 2011; Horan et al., 2012). The findings from the last couple of decades established the link between cognition and functioning. As will be seen in the next section on current studies, the questions have shifted from whether cognition is related to outcome to how cognition is related to outcome. Further, not all types of cognition are equally important when it comes to navigating the real world.

1.3.3. Cognition and interventions
Once it was established that cognition is a core feature of schizophrenia and that it is related to functional recovery, it followed naturally to ask whether treatments can enhance cognition. After all, if cognition was holding people with schizophrenia back from full participation in their daily lives, then cognition enhancement should eliminate this barrier. Intervention studies for cognition in schizophrenia can be grouped into two general categories that we will consider separately: cognitive remediation and psychopharmacology.

The studies on cognitive remediation from the 1980s and 1990s included highly focused experimental manipulations on a particular task, as well as broad rehabilitation programs that borrowed heavily from cognitive rehabilitation with brain-injured patients (Ben-Yishay et al., 1985; Green, 1993, 1998). For experimental manipulations, investigators explored the modifiability of performance on cognitive tasks (e.g., reaction time, problem solving, vigilance, verbal memory) using a range of approaches (such as coaching, monetary reinforcement, or instructions on performance strategies). For example, the Wisconsin Card Sorting Test was the testing ground for a variety of manipulations – results usually showed that patients’ performance can be improved (Goldberg et al., 1987; Green et al., 1992). These studies demonstrated that the performance deficits were not fixed, and also that the improvements sometimes persisted over time.

In contrast to the focused efforts to demonstrate modifiability on a task, more comprehensive and longer-lasting cognitive programs were also applied to schizophrenia patients (Brenner et al., 1990; Hogarty et al., 2004; van der Gaag et al., 2002). These programs were usually applied to small groups of patients and were extensions of the psychiatric rehabilitation programs. Beyond the typical procedures and structure of psychiatric rehabilitation, they included cognitive exercises that could be done in the group format.

These early approaches might appear overly focused (for the task manipulations) and less than novel (for the rehabilitation programs), but they established the ground work for later studies by demonstrating: 1) that task performance for schizophrenia patients can be modified, even on tasks that reflected core and relatively enduring impairments, and 2) the training exercises were well tolerated by patients, similar to other ongoing psychosocial interventions.Research Trail – Schizophrenia Essay

Regarding psychopharmacological approaches to cognition enhancement in schizophrenia – it started with a mirage. With the introduction of second-generation antipsychotic medications, many people (including the authors of this article) thought they had cognitive benefits when compared to first-generation medications. Initial suggestions of this effect came from examining patients who were placed on clozapine, and who showed cognitive benefits in some cognitive domains and not others (Goldberg et al., 1993; Hagger et al., 1993). Research Trail – Schizophrenia Essay  Evaluations of the cognitive effects of risperidone and olanzapine followed as they were introduced to market (Green et al., 2002; Purdon et al., 2000). Comparisons of second- to first-generation medications (some controlled and some not) added support to the idea that the more recent medications had cognitive benefits (Harvey and Keefe, 2001; Woodward et al., 2005). However, there were also some warning signs. First, the interpretation of the results was limited by relatively small sample sizes, and many of the earlier studies were uncontrolled. Second, concerns persisted that the doses of the medications were not well-matched (with relatively higher, and perhaps more sedating, dosing for the first-generation medication). These problems were addressed more directly in recent studies that are covered in the next section.

Almost all of the focus on psychopharmacology was on second-generation medications, as opposed to novel drugs with distinctly different mechanisms of action. In retrospect, this tunnel vision was unfortunate. However, there are several possible reasons for it: First, the introduction of second-generation medications generated genuine optimism about previously unmet treatment needs, including cognition and negative symptoms. There was a hope (or even an expectation) that the clinicians could get all the treatment needs for schizophrenia met in a single pill. Second, because these drugs were on the market (or close to coming on the market), pharmaceutical companies had an interest in funding investigator-initiated grants to demonstrate the full range of effects. Finally, there was a scientific basis to expect cognition enhancement. For example, animal studies indicated that second-generation medications could reverse induced cognitive deficits in a way that first-generation medications could not (Young et al., 2009). So, it was not entirely a mirage; but it turned out to be overly optimistic.

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2. Cognition in schizophrenia: present
Current research on cognition in schizophrenia naturally has grown out of its past. There are many areas of investigation at the present that clearly define the field. These include the definition and assessment of social cognition, cognitive and affective neuroscience, treatment of cognitive and social cognitive deficits, and the influences of genomic factors on cognition and its end-product in schizophrenia, everyday disability, and phase of illness. We will discuss each of these domains briefly.

2.1. Social cognition
Social cognition refers broadly to the domains of cognitive functions that are employed in socially relevant situations (Harvey and Penn, 2010). These include emotion processing, social perception, theory of mind/mental state attribution, and attributional style/bias, as well as more complex and developing concepts such as social metacognition (Pinkham et al., in press). It is clear that social cognition is of considerable importance for understanding social outcomes (Couture et al., 2006), with the correlation between impairments in social cognitive processes and functional outcomes more substantial than the correlations between neurocognitive deficits and these same outcomes (Fett et al., 2011). The study of social cognition is quite robust, in that more articles on social cognition are submitted to journals such as this one than articles focused only on neurocognition.Research Trail – Schizophrenia Essay

At the same time, the study of social cognition is in some ways less developed than that of neurocognition. A National Institute of Mental Health (NIMH) task force concluded that the domains of social cognition were less well defined than in neurocognition and that, as outcomes measures, many social cognitive tasks have some major deficiencies (Green et al., 2008). These include poor psychometric properties, and apparently similar outcome measures with minor variations, but few comparisons among them. In fact, an expert survey of social cognition produced 168 different domains and 108 different outcomes measures, with many of these domains and measures being very closely related to each other (Pinkham et al., in press). The similarity of many of these measures to each other has led to challenges in direct comparisons of their usefulness, as many of these assessments have overlapping content. Several efforts are underway to identify optimal social cognition measures and these studies will add clarity to the field.Research Trail – Schizophrenia Essay

2.2. Cognitive, social, and affective neuroscience
Considerable progress has been made regarding the functional and structural neuroimaging of cognition in healthy samples. The increased understanding of normal regional brain activity and functionally connected neural networks has been applied to developments in schizophrenia research. For example, the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) Initiative attempted to validate selective cognitive tests that are tied to specific neural networks and subprocesses (Carter and Barch, 2007).Research Trail – Schizophrenia Essay A data-collection extension of this initiative developed 4 performance-based tasks and examined their correlation with measures of both everyday functioning and performance-based measures of functional capacity (Gold et al., 2012). Although the correlations among indices of disability and performance on these measures were modest, the fact that this initiative could identify highly selective cognitive measures that were linked to specific neural systems reflects the substantial progress in this area.Research Trail – Schizophrenia Essay

Aside from cognitive neuroscience, the rapid emergence of social and affective neuroscience is now influencing schizophrenia research (Ochsner, 2008). These domains of inquiry focus on the neural substrates of social and emotional processes in healthy and impaired populations. For example, considerable work has gone into the patterns of neural activation during identification of facial emotion in schizophrenia (Anticevic et al., 2012; Taylor et al., 2012). Given the prominence of social processing and affective impairments in schizophrenia, this research direction can help to identify underlying neural abnormalities that give rise to social and emotional functioning.Research Trail – Schizophrenia Essay There are also rich possibilities to examine the intersection of cognition and emotion, including whether emotion dysregulation is associated with difficulties regulating cognitive efforts, the cognitive impact of negative or traumatic emotional experiences, and the impact of differences in emotional reactivity on the ability to perform cognitive operations. In addition, examination of underlying commonalities and differences in brain activation during emotional and cognitive tasks could inform treatments jointly aimed at emotional factors and cognitive deficits. Overall, social and affective neuroscience are expanding rapidly in basic behavioral science, and they are well positioned to shed light on the neural basis of both social and motivational problems associated with schizophrenia (Green et al., 2013).Research Trail – Schizophrenia Essay

2.3. Treatment of cognitive and functional deficits
Interventions targeting the disability of schizophrenia have been attempted for decades as described above. However, many interventions were aimed at social, vocational, and residential skills deficits in the absence of any interventions aimed at cognition. As cognitive impairments are primary correlates of functional deficits, it stands to reason that cognitive deficits might well underlie the skills deficits that lead to disability and might be “rate limiters” of treatment improvements. Meta-analyses of interventions aimed at disability reduction have suggested that, in general, treatment of cognitive and skills deficits should proceed in parallel to yield functional benefits (Wykes et al., 2011).Research Trail – Schizophrenia Essay

Cognitive remediation therapies have made substantial gains in the past two decades. Advancing past repetitive drill and practice interventions, the current cognitive remediation interventions share several critical features. They include dynamic difficulty titration, elimination of focus on “training the test”, feedback and encouragement, and a user-friendly interface with visually appealing graphics. These features combine to promote engagement and levels of adherence with treatment that are greater than before.Research Trail – Schizophrenia Essay

Training on specific cognitive skills is consistently found to be effective for improving cognition, but not necessarily for improving functioning. Studies of both comprehensive rehabilitation interventions and targeted skills training programs show that short term treatments generally show functional gains only when additional skills training is included (e.g., Bell et al., 2008; McGurk et al., 2007).Research Trail – Schizophrenia Essay This situation may be offset by findings that substantial doses of cognitive remediation (50 hours or more) are associated with both substantial cognitive changes (cognition change of up to d N 0.80) and improvements in functional skills (Fisher et al., 2009). Clearly an important issue to be resolved is whether a substantial dose of cognitive remediation can by itself improve daily life. In other words, does an improvement of 10 IQ points yield functional gains if the time frame for detecting these gains is long enough? It will be important for regulatory approval (and payer participation) to know whether concomitant skills training programs are necessary to realize the full benefits of cognitive remediation.Research Trail – Schizophrenia Essay

An important related issue concerns approval by regulatory agencies for treatments for cognition in schizophrenia. The overall goal of the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Initiative was to construct a regulatory pathway for cognitive enhancement (Marder and Fenton, 2004). Although MATRICS was aimed at pharmacological treatments, there does not appear to be a substantial distinction in the approval process for pharmacological and remediation-oriented interventions.Research Trail – Schizophrenia Essay At present both pharmacological and remediation-oriented strategies are under consideration for approval, though none have been approved so far. Pharmacological interventions would be considered as therapies added to a foundation of antipsychotic treatment for symptom management. Cognitive remediation interventions delivered with a computer, in person, or remotely would be considered to be medical devices and would be approved accordingly. As treatments are approved for cognition, one of the critical issues is the extent to which payers or regulators will expect to see functional gains to maintain approval for treatments with pharmacological or remediation-focused cognitive enhancing treatments.Research Trail – Schizophrenia Essay

2.4. Genomic influences on cognition
Studies of the genomic influences on schizophrenia represent a large share of the research allocation on the condition, with samples of patients in the tens of thousands. Cognitive deficits are clearly central to the illness and meet several critical criteria for being considered as important “endophenotypes” (Braff et al., 2007). They are stable, present in attenuated form in relatives, presumed to be genetically simpler than the illness phenotype, and measured with high reliability. In addition, they are among the most heritable of all illness-related traits, at least in families affected by severe mental illness.Research Trail – Schizophrenia Essay

The heritability of a variety of cognitive functions in families of people with schizophrenia been demonstrated in a multiple studies (Gur et al., 2007). Memory, attention, and executive functions seem to have a strong familial component that is substantially heritable. In addition, while disability is a complex phenotype, the skills underlying disability may be less complex. The components of disability, including everyday living skills and employment appear to be quite heritable behavioral traits (McGrath et al., 2009). The skills that underlie disability include cognition, as well as the ability to perform cognitively demanding everyday living skills.Research Trail – Schizophrenia Essay

Previous studies have identified genomic variation associated with cognitive endophenotypes (Greenwood et al., 2011). These include verbal memory, working memory, indices of attention / vigilance, and social cognitive processes. Further, sensory gating endophenotypes, such as P50 suppression and startle blink responses, also have strong genomic linkages. The full value of these findings will depend on their replication, and several related studies are in process.Research Trail – Schizophrenia Essay

2.5. Functional capacity
The study of functional capacity has increased substantially in the last decade. This concept refers to the ability to perform functionally relevant skills, including those relevant to social, vocational, and residential functions (Harvey et al., 2009; McKibbin et al., 2004). Multiple sophisticated performance-based assessments have been developed (Green et al., 2011b), including computerized assessments described for the first time in this issue. Several studies have suggested that these skills may be more proximal to real-world disability than cognitive deficits and they share features with cognitive deficits that suggest they are core features of the illness: stability over time, minimally associated with symptoms, and similarities cross-culturally.Research Trail – Schizophrenia Essay

Further, impairments in functional capacity performance meet criteria for an endophenotype, including substantial temporal stability (Light et al., 2012) and low levels of correlation with clinical symptoms (e.g., Bowie et al., 2008). Further, functional capacity scores appear to be minimally related to environmental support (Harvey et al., 2009), suggesting that having more support while performing these skills does not influence the likelihood that people with severe mental illness can perform them with competence. However, as shown recently, limited opportunities for experience in demonstrating skills can contribute to functional skill deficits on these tasks (Holshausen et al., in press).Research Trail – Schizophrenia Essay

An important consideration is the suggestion that functional capacity and neurocognitive skills may both reflect a larger common trait that we can call “ability.” Several studies with different samples have suggested that there may be one ability trait that cuts across tasks labeled “neurocognitive” and those designated as “functional” (Harvey et al., 2011). Although the types of tasks are quite different, they can be modeled in a way that both connect to one underlying trait in statistical models (Green et al., 2012). Further, cognitive and functional capacity indices were equivalently stable and similarly associated with the single factor over 6-week and 6-month follow-up assessments using sophisticated statistical analyses (Harvey et al., 2013).Research Trail – Schizophrenia Essay

2.6. Phase of illness
Previously, there was little need to discriminate the phase of illness of the patients. If schizophrenia developed, it stayed around and it may have actually worsened. Now we can detect risk states earlier, although imprecisely, and are better able to differentiate the effects of treatment, duration of illness, and are early course of illness on cognitive functioning (Cannon et al., 2008). Now we clearly know that the signature of cognitive impairment is not markedly different prior to the onset of diagnosable illness. We also know that, in the absence of the relatively rare phenomenon of nearly complete treatment resistance in older age, there is little consistent evidence of cognitive decline (Harvey et al., 2010).Research Trail – Schizophrenia Essay

Groups are also working on identifying cognitive predictors of conversion from what looks like a schizophrenia prodrome to a psychotic state. The literature suggests that probably we are looking too late: individuals who are considered to be prodromal and already have cognitive deficits seem more likely to convert to psychosis; those without the deficits seem at lower risk (Seidman et al., 2010). One of our goals in the next decade will be in closing the gap on convergence between clinical and cognitive deficits in cases who are about to convert to psychosis and to “get there earlier” in the cognitive prediction side.Research Trail – Schizophrenia Essay

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3. The future – educated guesses
The baseball manager Yogi Berra famously observed that “It’s tough to make predictions, especially about the future.” Hence, the authors of this article have little to gain, and can only be proved wrong, by sticking our necks out and making predictions, especially about the future. Undaunted, we will make some general guesses at this point. The subsequent trend lines for research in cognition and schizophrenia will be played out in the pages of this new journal, and we will eventually know what we got right and what we got wrong.Research Trail – Schizophrenia Essay

One general rule is that research into cognition in schizophrenia follows, often closely in time, developments in basic biological science. Hence, as advances in basic science (e.g., inflammatory markers, optogenetics, epigenetics, pluripotent stem cells, advanced neuroim-aging paradigms, etc.) are applied to schizophrenia, they will also be applied to the cognition of schizophrenia. Once a biomarker is found to be associated with the disease, the next step frequently is to evaluate whether it is related to cognitive impairment. Herein lies one of the advantages of cognition compared with other features of the illness – it is seen as more directly related to known brain circuits. Beyond this general tendency to essentially travel on the coattails of neuroscientific advances, we can identify a few promising directions.Research Trail – Schizophrenia Essay

3.1. Treatment – a 3rd path
Treatments for cognition in schizophrenia fall into two categories: training interventions (such as cognitive remediation), and psycho-pharmacology. However, we may soon see a focus on a third approach: neurostimulation. Such approaches include transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) (Minzenberg and Carter, 2012). These approaches attempt to change cognition by directly stimulating the brain. In TMS a strong, transient magnetic field is applied to the scalp from a hand-held coil.Research Trail – Schizophrenia Essay That application creates electric current in the brain, which alters the membrane potential and leads to neuronal firing. In tDCS a low-intensity direct current is applied to the scalp, which modulates neuronal excitability (either higher or lower, depending on polarity), but does not cause firing directly. The beneficial effects of these methods sometimes appear to be long lasting, but the results are variable (Guse et al., 2010). The value of these approaches alone, or in combination with other treatment modalities, is likely to be a focus in coming years.Research Trail – Schizophrenia Essay

3.2. The interface of motivation and cognition
It is common to view cognition and motivation as separate spheres. Indeed, motivation is much more linked to negative symptoms, such as asociality and avolition. But recent formulations suggest that the two domains may be linked. For example, self-reported intrinsic motivation has an effect on the benefits of cognitive remediation (Medalia and Brekke, 2010).Research Trail – Schizophrenia Essay In addition, it is possible that impairments in cognition and social cognition, lead over time to decreases in motivation that we see as negative symptoms, including asociality and anhedonia (Green et al., 2012). Recent developmental models suggest that the two largest unmet treatment needs in schizophrenia, cognition and motivational negative symptoms, are related, and may emerge at different points in development (Beck et al., 2009; Grant and Beck, 2009). That is, long-standing cognitive and social cognitive problems could lead to expectations (dysfunctional beliefs) in which the person learns to not expect to be successful or to enjoy interactions. These beliefs, in turn, lead to motivational negative symptoms. The interaction and overlap between the science of cognition and the science of motivation present wide open areas of exploration for psychopathology.Research Trail – Schizophrenia Essay

3.3. Technology as a problem and a solution
Perhaps the most ubiquitous feature of worldwide culture in the 21st century is technology. Television shows for children feature dogs who have blogs and nearly every aspect of life is technology driven. As a result, elderly individuals and people with severe mental illness are expected to perform on-line banking and ATM tasks, and to engage in internet or phone voice menu tasks to schedule appointments and refill predictions (Harvey and Keefe, 2012). In many cases there are no alternatives offered other than internet-based services. This relentless change creates a disadvantage for those with less experience or less ability, but may, paradoxically, offer opportunities.Research Trail – Schizophrenia Essay Technology can be less expensive and in an era when health costs are a paramount concern, technology may offer an opportunity for service delivery that would never be possible if in-person interventions were required. For instance, remotely delivered cognitive enhancement interventions have recently been shown to have clinical efficacy (see this issue). Thus, in contrast to the classical model of bricks and mortar clinic, receptionist, therapist, and group interventions, people with severe mental illness could be provided with a low priced device loaded with software and be prompted and cued remotely to self-administer the intervention. This type of intervention has been applied with success for years in aging populations with low levels of experience with technology (Czaja et al., 2006).Research Trail – Schizophrenia Essay

3.4. Applications of animal models
It is obvious that animal models of cognition have had a profound impact on our understanding of human cognition. However, they have had a limited impact on the study of cognitive impairment in schizophrenia.Research Trail – Schizophrenia Essay To understand the multitude of genetic and molecular mechanisms associated with cognitive impairment in schizophrenia, neural circuit assays (i.e., behavioral tasks known to depend on specific circuits) are needed, and those often come from animal models (Moore et al., 2013). Such models are valuable for neural demonstrations of construct validity (whether the identified cognitive processes are homologous between species), as well as pre-clinical indications of predictive validity (whether a drug is likely to have a therapeutic benefit in human patients) (Keeler and Robbins, 2011). Given an increasing focus on construct validity at the neural level, and increasing examples of successful translation and back-translation, this area could assume a much larger emphasis for the study of cognition in schizophrenia in coming years.Research Trail – Schizophrenia Essay

3.5. Diagnoses
An intriguing, though perhaps unsettling, thought about the future of cognition research in schizophrenia is that it might not exist at all. That is, it might not be on schizophrenia per se. One of the implications of the NIMH Research Domains Criteria (RDoC) Project is that specific diagnoses, such as schizophrenia, will not fit into the growing knowledge from neuroscience, and instead the field will move to brain-based constructs that cut across diagnostic boundaries (Cuthbert and Insel, 2010; Insel et al., 2010). A better understanding of these domains might lead to a reorganization of the diagnostic groupings in a way that better carves psychopathology at its neuroscientific joints. In such a reorganization, schizophrenia as a separate disorder could be clumped into a mixed category of psychoses, or split into the meaningful and biologically validated subtypes.Research Trail – Schizophrenia Essay

It is easy for this pendulum to swing too far in either direction. A narrow focus on biomarkers or RDoC dimensions risks an overreliance on reductionism that overlooks important higher-order and functional aspects of the disease. In contrast, a narrow focus on clinical syndromes and traditional diagnostic categories risks an overreliance on surface-level clinical features and a continued failure to identify neurobiologically meaningful dimensions or subtypes.Research Trail – Schizophrenia Essay

Resolving this balancing act will not occur immediately, and schizophrenia is not disappearing as a diagnosis any time soon. Instead, there will be continued efforts to start with existing diagnoses and to revise them incrementally. In this mode, cognition might become a more central part of schizophrenia in diagnostic systems. That very nearly happened for the latest version of the Diagnosis and Statistical Manual (DSM-5) in which cognition was one of several dimensions that was initially slated for inclusion, but ultimately moved out of the main body of the text to Section 3, meaning that it requires additional study (Barch et al., 2013). In contrast to DSM, the proposed revision for the International Classification of Diseases (ICD-11) includes level of cognitive impairment as a specifier (Gaebel, 2012). If that change in ICD-11 is maintained through the field trials and revision process, it will mark the first time that clinicians internationally will be asked to note and record the cognitive status of schizophrenia patients as a routine part of evaluation.Research Trail – Schizophrenia Essay

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4. Conclusions
Schizophrenia in the past was a grim diagnosis with a poor prognosis. At the present time, it can probably be better described as a serious condition, with plenty of reasons to be hopeful. The breadth and depth of valuable information on this disease, as in other areas of science, is experiencing rapid, almost exponential, growth. We probably learned more about schizophrenia in the past 10 years than we learned in the previous 100. Like any other area of biomedical science, the sheer volume of the scientific output, as well as the rate of change, is daunting and intimidating. Most of us are conducting research on topics that did not exist, or were not discussed, when we were in training. The future holds both considerable promise and substantial challenge. This new journal will track those developments, help to organize the massive amount of information, and provide a forum for their dissemination and impact.Research Trail – Schizophrenia Essay

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Role of Funding Source


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There are no other contributors other than the authors.
Conflict of interest

Dr. Green has been a consultant to AbbVie, Biogen, DSP, and Roche, and he is on the scientific advisory board of Mnemosyne. He has received research funds from Amgen. Dr. Harvey has received a contract research grant from Genentech, and has received honoraria for consulting or travel support from AbbVie, Boeheringer Ingelheim, En Vivo, Genentech, Otsuka America, Roche, Sunovion, Shire, and Takeda.Research Trail – Schizophrenia Essay

Longitudinal data suggest heterogeneity in the long-term course of schizophrenia. It is unclear how older adults with schizophrenia perceive changes in their experience of schizophrenia over the lifespan. We interviewed 32 adults aged 50 years and older diagnosed with schizophrenia (mean duration 35 years) about their perceived changes in the symptoms of schizophrenia and functioning over the lifespan. Interview transcripts were analyzed using grounded theory techniques of coding, consensus, co-occurrence, and comparison.Research Trail – Schizophrenia Essay The study was conducted by a research partnership involving a multidisciplinary team of academic researchers, community members, and mental health clients engaged in all aspects of study design, interviewing, and analysis and interpretation of data. Results revealed that, in regard to early course of illness, participants experienced confusion about diagnosis, active psychotic symptoms, and withdrawal/losses in social networks. Thereafter, nearly all participants believed that their symptoms had improved, which they attributed to increased skills in self-management of positive symptoms. In contrast to consistency among participants in describing illness course, there was marked heterogeneity in perceptions about functioning.Research Trail – Schizophrenia Essay Some participants were in despair about the discrepancy between their current situations and life goals, others were resigned to remain in supported environments, and others working toward functional attainments and optimistic about the future. In conclusion, middle-aged and older adults with schizophrenia believed that their symptoms had improved over their lifespan, yet there was substantial variability among participants in how they perceived their functioning. Functional rehabilitation may need to be tailored to differences in perceptions of capacity for functional improvement.Research Trail – Schizophrenia Essay

aging, psychosis, disability, qualitative research, quality of life
Topic: heterogeneity adult mental health middle-aged adult perception schizophrenia diagnosis rehabilitation psychotic symptom elderly community qualitative research social networks self-management life span consensus
Issue Section: Regular articles
The traditional view of the course of schizophrenia has been that of progressive decline,1 yet cross-sectional and longitudinal studies indicate substantial heterogeneity in the long-term course of schizophrenia.2–6 Collectively, studies of community-dwelling outpatients indicate a surprising degree of stability in cognitive abilities,7–9 with little evidence that cognitive ability declines at a faster rate compared with normal subjects.Research Trail – Schizophrenia Essay In addition, symptoms prominent at the onset of the disease may diminish in late adulthood,4,10 and a small subgroup of older adults experience sustained remission from schizophrenia.11 Yet, some subgroups of patients, such as those who are chronically institutionalized, display progressive worsening in cognitive ability, functioning, and are unlikely to attain remission.12 In regard to functioning, cross-sectional studies of age effects in subjective indicators of functioning, such as health-related quality of life (HRQOL), have been inconsistent, with some showing a positive effect of age on mental HRQOL,13 no correlation with age,14,15 or a negative relationship.16,17 Better understanding of the determinants of heterogeneity in how older persons with schizophrenia perceive and adjust to their illnesses may help direct preventive and rehabilitative efforts.Research Trail – Schizophrenia Essay

Largely missing from the research described above is the perspective of the older patients themselves about whether and in what ways they recognize changes in their illness over time. Although life chart methods have been used in psychiatric illnesses to specify timing in illness course,18 there are few validated instruments to solicit perceptions of lifespan changes in severe mental illness.Research Trail – Schizophrenia Essay For this reason, qualitative methods provide a useful approach to assessing individual perceptions of lifespan course of schizophrenia. However, only one study, to our knowledge, has used qualitative methods to address perspectives on illness course in schizophrenia19 and that study interviewed 6 older women with schizophrenia. The limited number of qualitative studies in older adults with schizophrenia may be due, in part, to concerns about whether the interviewees can provide meaningful information to open-ended queries, especially given concerns about their insight and cognitive impairment. Nevertheless, in 2 previous qualitative studies that addressed different subject matter, we have found that qualitative interviews of older adults with serious mental illness are feasible and informative.20,21.Research Trail – Schizophrenia Essay

The aim of this study was to gain an understanding of the perspectives of older adults with schizophrenia about if and how their experience of the illness had changed over the lifespan as well as their expectations for the future. The study was conducted by a research partnership involving a multidisciplinary team of academic researchers, community members, and mental health clients engaged in all aspects of designing the study, research interviewing, and analysis and interpretation of data.Research Trail – Schizophrenia Essay

Study Participants
Study participants were recruited from the database of the University of California, San Diego (UCSD) Advanced Center for Innovation in Services and Intervention Research, that focuses on late-life psychoses, and is funded by the National Institute of Mental Health. Participants were recruited by informing other Center investigators of the study and through dissemination of study information via Center recruitment staff. A total of 32 individuals were scheduled and interviewed, based on accepted sample size estimates for qualitative research.22,23.Research Trail – Schizophrenia Essay

A maximum variation sampling procedure was adopted24 to enable diversity in age, gender, ethnicity, and living situation. Moreover, study exclusion criteria were kept to a minimum in order to enroll a diverse sample. The minimum age to participate in the study was 50 years. Participants were excluded if they could not demonstrate capacity to provide informed consent, were currently hospitalized in an inpatient setting or a nursing home, or were experiencing any acute or chronic illness that would substantially diminish their ability to participate in an interview study (eg, if they had been previously diagnosed with dementia). Based on their participation in previous Center research studies, all participants had previously undergone structured diagnostic assessment, and diagnoses of schizophrenia were confirmed by a board-certified psychiatrist or psychologist in consensus meetings. All participants had to consent to audio taping of the interviews and be willing for deidentified portions of the transcripts to be reported in scientific publications. This study was approved by the UCSD Institutional Review Board, and a written informed consent was obtained from each participant.Research Trail – Schizophrenia Essay

After providing informed consent, participants were interviewed at UCSD or at their place of residence, depending on their preference. The meeting consisted of a semistructured interview and a demographic questionnaire.Research Trail – Schizophrenia Essay

The interview was developed in collaboration with 2 community members (a consumer [S.S.] and the parent of a consumer [G.H.]) and 2 academic researchers (C.D., M.H.). The community members held leadership roles in the San Diego Affiliate of the National Alliance on Mental Illness. All the study team members were involved in designing, conducting interviews, analysis, and interpretation of qualitative data. All interviewers, including community members, attended two 3-h training meetings which covered: (1) the goals of the project, (2) procedures and interviewing techniques, and (3) participant and interviewer safety. They were also taught procedures for obtaining informed consent, introducing ideas to be discussed, moderating the discussion, handling difficult participants, and leading the interview to a conclusion.25

Based on consensus meetings, a semistructured interview format was developed, and all participants were asked the following questions with follow-up probes as appropriate:Research Trail – Schizophrenia Essay

Past: What was it like when you first started experiencing symptoms of schizophrenia?

Changes: How has your view of schizophrenia changed over your lifetime? Do you believe that your condition has changed over time?

Current: How would you describe your life at the moment? Can you tell me about things in your life that make your life better? Are there particular areas in your life that you feel make things difficult?

Future: What are your expectations for the future? If it “all worked out,” what would life be like?Research Trail – Schizophrenia Essay

The interviews were designed to be open-ended so that interviewees could elaborate on other areas that they felt were important to describing schizophrenia over their lifespan. We included no specific prompts regarding life domains related to quality of life (eg, finances and medical illnesses) and avoided steering the discussion toward topic areas specified by the interviewer. The average interview lasted between 45 min and 1 h. Interviews were audiotaped and transcribed. Following the semistructured interview, the participants were asked to provide basic demographic information (age, gender, ethnicity, education, and living situation) along with the age of onset of symptoms and of diagnosis.Research Trail – Schizophrenia Essay

Data Analysis
Audiotapes were transcribed and were processed using the grounded theory-based approach of “coding consensus, co-occurrence, and comparison” described by Dennis et al.26 Transcripts were independently coded by 2 coders (S.S. and C.D.) to develop a typology of responses, which was subsequently developed into a coding scheme covering the key domains identified in the interviews. Initially, codes corresponded to the root questions in the semistructured interview, and segments of text ranging from clauses to paragraphs were assigned codes by independent coders.Research Trail – Schizophrenia Essay A consensus meeting was held between coders, and any disagreements in assignment or between codes were resolved to create a final coding scheme. The same units of text could be assigned to multiple codes. Because the aim of the study was to understand the course over time of schizophrenia, all text units were assigned a code corresponding to life domain (eg, living situation and relationships) as well the time frame (ie, prediagnosis, from diagnosis until now, current, changes over time, and future). Three interviews were randomly selected and coded independently by the coders to estimate intercoder reliability.Research Trail – Schizophrenia Essay Initially, the percent agreement between coders was 60%, but upon inspection, a large proportion of the disagreements was found to lie in the assignment of time frame, specifically prediagnosis and diagnosis until the present. Once these 2 codes were merged, the percent agreement was 75%, indicating an acceptable degree of concordance between coders.27

Codes from the transcripts were entered into a qualitative software package (QSR NVivo) and arranged in a treelike structure connecting transcript segments grouped into separate categories or “nodes.” These nodes and trees were used to examine the association between different a priori and emergent categories and to identify the existence of new, previously unrecognized categories. The number of times these categories occurred together, either as duplicate codes assigned to the same text or as codes assigned to adjacent texts in the same discussion, was recorded and specific examples of co-occurrence illustrated with transcript texts. Finally, through the process of constantly comparing these categories with one another, the different categories were further condensed into broad themes.Research Trail – Schizophrenia Essay

Sample Characteristics
Sample characteristics are presented in table 1. The mean age of the sample was 55.7 years (SD = 4.1 years; range 50–72). The sample distribution included 40.6% women and a roughly even distribution of individuals residing independently vs in board and care homes. Median income fell below the poverty line (<$10 000), and only 13.3% of participants were currently employed. Participants had experienced the symptoms of schizophrenia for, on average, 35 years.Research Trail – Schizophrenia Essay

Table 1.
Sample Characteristics (n = 32)

Range Mean (SD) or % (n)
Age 50–72 55.7 (4.1)
Gender (% female) — 40.6% (13)
Race/ethnicity —
Caucasian 67.7% (22)
African American 12.9% (4)
Hispanic/Latino 9.7% (3)
Other 9.7% (3)
Education 8–20 13.3 (SD = 27)
Living situation —
Independent living 56.2% (18)
Board and care facility 43.8% (14)
Marital status —
Single, never married 46.9% (15)
Married 18.8% (6)
Divorced/separated 34.4% (11)
Employment status (currently employed) — 12.9% (4)
Income (median) — <$10 000
Age of onset of illness 3–48 20.5 (10.4)
Age of first diagnosis 10–55 25.7 (11.1)
History of any psychiatric hospitalization — 93% (30)
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Qualitative Results
Codes were identified representing life domains as well as the 3 lifespan segments (onset and early course, middle course, current, and future outlook). Using these codes and the constant comparison technique, themes emerged within the sections of the semistructured interview. We assessed these themes with respect to perceived changes over time in the course of illness. Figure 1 summarizes the main themes derived from the interviews.Research Trail – Schizophrenia Essay

Fig. 1.
Perceptions of the Course of Schizophrenia Based on Qualitative Interviews (n = 32).
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Perceptions of the Course of Schizophrenia Based on Qualitative Interviews (n = 32).

Symptom Onset and Early Course; Upheaval
Participants described the early course of their illness in terms of “feeling different” during childhood, along with chaotic social and family environments (eg, unstable living situations, traumatic experiences, family members with mental illnesses).Research Trail – Schizophrenia Essay

“When I was, when I was in Special Ed classes and voices would talk to me a lot, you know, and I’d tell them not to bother me no more. And a couple of times that I did that it disappeared for a few minutes. Then it came back though. And then it was tragic after that.”Research Trail – Schizophrenia Essay

“I wanted to stay at home all the time. I didn’t want to go out. My dad had to force me to go outside to play with the kids because I was afraid they were going to laugh at me, and make fun of me.”

Losses were frequent—eg, several women were forced to give newborn babies up for adoption, or to relinquish custody of older children, never to see them again. Participants described being confused about the symptoms and public reactions to schizophrenia. “Escapism” was a common response to these troubling situations. This included abusing substances and/or suicide attempts.Research Trail – Schizophrenia Essay

“But when you are labeled a schizophrenic or you have psychosis and you don’t understand it because you didn’t learn about it prior to and you’re like, all of a sudden you’re in this nightmare, and with nobody to help you because nobody understands, nobody’s in it with you. The whole world is dead; you’re the only one alive in this big graveyard, which is the world. You have to survive with no money and no place to sleep and all these dead people trying to kill you or whatever, rob you of your sanity is more like it, same thing.”Research Trail – Schizophrenia Essay

“I couldn’t understand it and that was hard for me and I wanted to commit suicide. Yeah, and I tried. I got in the car once and drove really fast and tried to wreck the car, but then I finally came to my senses that I already had a baby and I didn’t want to leave the baby motherless.”Research Trail – Schizophrenia Essay

In terms of functional milestones, 15 participants had never married; the remainder reported experiencing significant marital discord, including emotional abuse, fear, and complete family upheaval. Some individuals had been able to manage their illness well enough to pursue a higher education (8 individuals had some college education). Some individuals worked intermittently; a few were able to hold down jobs for months and even years but were forced to quit when their symptoms became unmanageable.Research Trail – Schizophrenia Essay

Financial support was undependable and often a function of the individuals’ ability to advocate for themselves in their dealings with social services agencies.Research Trail – Schizophrenia Essay

“I lived on the streets for quite a couple of years · · · because I didn’t know what to do with myself and I ran out of money to live with my mom and stepfather · · · and they kicked me out.”

Early experiences with treatment could be divided into self-initiated or forced, with the latter resulting from pressure from family members or law enforcement. Most participants described a series of trials of different medications, with periods of nonadherence to the medication regimen because of lack of efficacy or side effects.Research Trail – Schizophrenia Essay

Middle Course: Adaptations to Symptoms
Participants described a lengthy period of transition after early experiences with schizophrenia, during which there were struggles with hospitalization, finding medications that worked, homelessness or incarceration, family disruptions, and often little or no support of any kind. However, the participants we interviewed described steps they took to adapt to schizophrenia, with most attaining symptom improvement and stable housing (either in a board and care facility or independent housing). The interviewees described gaining insight that helped improve their life situation; eg:Research Trail – Schizophrenia Essay

“In ’98, I was sitting in the courtyard in the unit I was on. I was smoking my cigarette and I looked up and saw this razor wire and I go, “Is this really what I want?” I’m talking to myself. “I’ve been here a long time. Am I really going to be here until I die?” I put out my cigarette and went to find my [counselor]. “I told her “I don’t want to die here, I don’t want to die [here], what can I do?”

Participants chose to take their illness seriously and to become more knowledgeable about it, which included motivation to acquire effective self-management skills.Research Trail – Schizophrenia Essay

“I learned to look at myself and do a little self-inventory on myself. I started learning things, and the more I learned, the more it was helpful to me.”Research Trail – Schizophrenia Essay

“With the illness, like I say, you know, as long as you’re willing and trying to get better, then I’m all for it. But if I wasn’t trying to get better or trying to make a life for myself, Lord knows where I’d be right now. Because no one was making me take this medication.”Research Trail – Schizophrenia Essay

Nearly all the participants felt that their symptoms became more manageable and less disruptive. The interviewees attributed these improvements to developing better coping abilities, adherence to a stable treatment regimen, and participation in group therapy-related activities. They accepted the need for medications to control their illness and recognized the importance of a collaborative relationship with a doctor whom they could contact when they felt that their symptoms were worsening.Research Trail – Schizophrenia Essay

The participants described a number of techniques they used to cope with the voices, including ignoring them, talking back to them and telling them to “shut up,” or using the television or radio to distract their attention.

“Yeah, I was able to change my way of thinking to the point where I can use the intelligence that God gave me to reason my way through this delusion of paranoia, which it is. People who hardly know me aren’t going to be talking about me.”Research Trail – Schizophrenia Essay

“Every time I pass a group of people · · · I think they’re talking about me · · · Then I realize that I’m able to reason my way through it and say, well, wait a minute, it doesn’t ring true. Why would they be talking about me?”

Middle Course: Losses in Social Relationships and Adaptations in Social Networks
Most participants described social isolation, whereas a few maintained regular contact with family members or remnants of their social network. With limited opportunities for socialization and the fear of being rejected or discriminated against, they were leery of interacting with people outside familiar environments. The interviewees often worried about displaying symptoms in public.Research Trail – Schizophrenia Essay

“I get around and I just isolate myself, because I don’t feel most people can understand or relate to what I have to say.”

The majority of individuals reported that they maintained some form of contact with their families, while some individuals had relatives they had not been in touch with for 20–30 years.

“Well, I did have the phone numbers of a lot of relatives in the family, but I sort of feel afraid to call them. I guess I sort of feel embarrassed about my illness, you know.”Research Trail – Schizophrenia Essay

However, some families were very supportive. Some moved to be closer to the participant to be able to provide support. A brother regularly refilled the minutes on the participant’s cell phone so that they could keep in touch. Moreover, peers had replaced social networks for many participants.Research Trail – Schizophrenia Essay

“The people here, we talk, we laugh, we joke, and they’re always there for me. If I feel bad, they’re always there to help me go through it together. And I think I feel better about myself now than I did when I was a kid.”

Present and Future Outlook
Whereas participants were consistent with each other in regard to their experience of symptom improvement, there were marked differences among participants in their appraisal of the present life situation and their outlook toward the future. We identified 3 subgroups of interviewees in regard to outlook: (a) with despair over lost opportunities (n = 6), (b) with resignation/acceptance of current situation (n = 16), and (c) with hope and optimism (n = 10). There were no significant differences between these groups in age, gender, ethnicity, age of onset, education, or living situation, although the small group sizes likely precluded detection of differences due to low power.Research Trail – Schizophrenia Essay

With Despair Over Lost Opportunities.
With increased understanding of their illness, some participants were regretful over their failure to achieve the goals they had once set for themselves.

“I criticize myself for not being smart enough to do certain things or to make more money or to have things that other people have.”

Diagnosed with schizophrenia when he was 17 years, a 52-year-old man described living with his sister (who also had schizophrenia) and their mother until 4 years before the interview when the mother passed away. He described a conversation with his sister:Research Trail – Schizophrenia Essay

“I asked her once, ‘Where did we go wrong, why are we in these Board and Care homes? · · · I feel like we’re in here because people have given up on us or we’ve given up on ourselves.’ ”

He wondered if receiving Social Security Income (SSI) at an early age had prevented him from doing more for himself:

“I wonder would I have tried to get a job or if getting SSI has kind of lost my will to survive because I’m getting money”. And again, “If I had my own apartment I might have a little more self-esteem. Living here, I feel like I’m here because I can’t help myself, like I’m hopeless. That’s why they put me here.”Research Trail – Schizophrenia Essay

Another 50-year-old man stated: “I feel like I have never lived enough · · · and as I keep going on this just keeps getting worse because I feel like I’m not living up to my expectations of what I thought my life was going to be. And I just, it just keeps getting worse as I get older. I just keep losing.”Research Trail – Schizophrenia Essay

With Resignation/Acceptance.
A subset of participants appeared to have accepted their situation, and they no longer compared themselves with “normal” people out in the community but rather to those who were doing worse.

“I have a roof over my head, I have food to eat and clothing and my computer and my stereo, and if I compare my life with some of those starving people in other countries, it’s like I’m living in heaven compared to them.” · · · There’s always somebody better off or worse off than yourself.Research Trail – Schizophrenia Essay

One 61-year-old woman described her current life in a board and care home, “you’ve got everything you want · · · and meals · · · I can go to bed anytime · · · and be lazy. I don’t have to talk · · · I am not in a locked facility.” She said that she missed “going out and doing things,” but chose not to.

Among the greatest barriers to making changes in this subset of participants were their financial limitations.Research Trail – Schizophrenia Essay

“I don’t think I’m in control of my future. · · · My financial situation controls it. You can only do so much on a limited budget · · · it looks the same every day, month after month.”

“I don’t really have long-term goals, not any more. I did at one time.”

With Hope and Optimism.
The third subgroup of participants were hopeful about the future and were attaining functional milestones for the first time in their lives. These individuals took pride in their ability to participate in normal activities.Research Trail – Schizophrenia Essay

“It’s now, like I say, in remission. I can lead a normal and productive life. I mean, I can do anything anybody else can do, you know? I can drive a car. How I was talking about responsibility, I can open bank accounts, I can get a new cell phone line, and I can function.”Research Trail – Schizophrenia Essay

Another interviewee taught a class on symptom management at a youth health center and also worked as a cashier,

“As long as my performance [at work] is ok, I’m fine · · · I never had three things at one time, a job, a car and a house, never. This is the longest I have ever kept a job, almost seven months, longest in my life since I was 23.”Research Trail – Schizophrenia Essay

The personal interviews we conducted with older adults with schizophrenia revealed a number of aspects of the experience of aging with this illness. Similar to previous cross-sectional and longitudinal reports that indicate improvement in the symptoms of schizophrenia, most of the participants we interviewed believed that the symptoms of schizophrenia, particularly the positive symptoms, were most severe in the early course of the illness and had improved over time.Research Trail – Schizophrenia Essay Participants attributed this improvement to their active development of self-management skills, detailing a variety of strategies used to cope with hallucinations and delusions. Interviewees had also made adaptations to social networks, with peers and facility staff replacing family relationships for some. Despite these consistencies among the participants, they differed from one another in their outlook toward the future. The interviewees were either distressed over the discrepancy between their life goals and their situation or resigned to accept their current level of independence and functioning or optimistic about and empowered by functional attainments. Overall, our study suggests that symptom improvement over the lifespan may be characteristic of community-dwelling patients with schizophrenia, yet elements of recovery (eg, optimism and hope) and attainment of functional milestones remain elusive for many.Research Trail – Schizophrenia Essay

This study has several limitations. The sample was restricted to middle-aged and older outpatients in one geographic region, all of whom were receiving treatment. Participants needed to be willing and capable of participating in an interview about their experience with schizophrenia, which by nature excluded participants with severe psychotic symptoms and people who did not want to participate in research. Therefore, these results may not generalize to institutionalized or inpatient populations or participants who are too symptomatic or cognitively impaired to participate in interviews.Research Trail – Schizophrenia Essay The small sample size made it difficult to compare responses between specific target groups, and there was heterogeneity within the sample. Finally, retrospective narratives about life changes are influenced by the present state of the participant, and it is certainly possible that state factors (eg, depressed mood) influence the recounting of lifespan trajectories.Research Trail – Schizophrenia Essay

Nevertheless, we found that all but one of the 32 interviewees described improvement in the personal impact of symptoms of schizophrenia, after experiencing the greatest degree of disruption and symptom severity in the early years of the illness. There are several theoretical explanations that have been proposed for improvement in schizophrenia in later life.Research Trail – Schizophrenia Essay It is likely that there is a survivor effect in that older adults with schizophrenia have avoided suicide and other causes of mortality, although long-term follow-up studies indicate that survivor biases may not fully account for cross-sectional differences.3 Normal age-related neurobiological changes, such as reduced activity in the dopaminergic system, may produce attenuation in severity of positive symptoms.9 Older adults may have less substance abuse comorbidity than their younger counterparts.28 Our qualitative study suggests that over the lifespan, individuals attain greater capacity to manage psychotic symptoms. Participants described increasing their acceptance and self-management abilities, which is consistent with the observation that medication adherence appears to be better among older vs younger patients.29 It is notable that the development of these skills was portrayed by participants as an active self-motivated process. It is likewise notable that participants were not free of symptoms, and many continued to experience active hallucinations or delusional thinking, consistent with other literature suggesting that maintenance of employment is possible even in the presence of positive symptoms.30 However, they were more able to engage in strategies that defused the impact of psychosis (eg, challenging the reasoning underlying paranoia), consistent with skills taught in cognitive behavioral therapy for schizophrenia.31 Therefore, many older people appeared to have successfully adapted to the symptoms of schizophrenia, and, in addition, some had adapted social networks to include peers and staff members to compensate for losses in indigenous social networks (although there may be a role for interventions aimed at strengthening indigenous social networks).Research Trail – Schizophrenia Essay

However, while the impact of the symptoms of the illness appear to lessen into older age, trajectories of functional recovery do not always follow this general pattern of improvement.32,33 Our qualitative study provides insight into potentially important psychological mechanisms that may accompany functional recovery. There is not general agreement concerning the definition of recovery,34 and it can be seen as a process or an outcome; however, a U.S. Substance Abuse and Mental Health Service Administration Consensus Statement definition of recovery is: “living a meaningful life in a community of his or her choice while striving to achieve his or her full potential.”35 In light of this definition, there were 3 patterns among interviewed participants.Research Trail – Schizophrenia Essay One participant subgroup expressed hopelessness in expectations about the future, despaired over lost opportunities over the lifespan, and experienced a significant discrepancy between their goals for the future and their current situation. As middle-aged and older adults, these individuals felt that they were “running out of time” to make functional improvements (eg, getting married). This subgroup may benefit from interventions and/or peer support centering on setting obtainable goals and reducing depressogenic cognitions such as self-blame. A second subgroup expressed a general resignation to their situation, expecting to stay in supported housing environments for the remainder of their lives, lacking a sense of control of their future, citing financial barriers to change.Research Trail – Schizophrenia Essay This group may benefit from education in ways in which they could overcome financial barriers,36 such as the Social Security Administration’s “Return to Work” program. Finally, a third subgroup of interviewees, who were hopeful about the future, described the new experience of attaining long-term goals (eg, employment) that had been long derailed by schizophrenia. Future studies should examine the experiences and practices of such people in order to determine how they managed to positively alter their life trajectories toward recovery.Research Trail – Schizophrenia Essay In sum, our qualitative study suggests that even if individuals learn to manage schizophrenia over its long-term course, only a proportion of them experience commensurate improvements in their capacity to attain functional recovery. In addition to the need to refocus interventions toward impacting functioning,37 this study suggests that different rehabilitative strategies may be needed to improve functional outcomes among people who do not believe they have the capacity to make functional changes vs those who are working toward functional change but believe they are failing at it. Finally, heterogeneity in the course of schizophrenia in regard to symptoms and functioning likely increases with age, as with increasing heterogeneity among unaffected people in many traits, and the divergence in perspectives on the future is consistent with increasing heterogeneity.Research Trail – Schizophrenia Essay

There were advantages in conducting this study with a community-based collaboration in which mental health consumers were involved in all phases of the study.38Community members volunteered a great deal of time and energy, and the study was accomplished with a minimal budget. Some aspects of the development and adaptation to a chronic illness are universal, and the perspectives of consumers were essential in developing the interview and extracting meaningful themes from participants during interviews and from transcripts. On balance, there is a need for enhanced interviewer training/support, in that the content of interviews was emotionally difficult for some consumer interviewers, and a formal support system should be established.Research Trail – Schizophrenia Essay

Compared with 1961, when sociologist Erving Goffman who interviewed residents of locked mental health facilities wrote “The application of stringent restrictions on self-expression and behavior, along with the threat of punishment, denied residents the opportunity to develop an independent sense of self,”39 the participants in our study were no longer subject to that degree of control.Research Trail – Schizophrenia Essay The interviewees appeared to have benefited from the system of care to the extent that they experienced subjective improvements in symptoms and some areas of functioning, which may provide hope for younger adults as they anticipate growing older with schizophrenia. Nevertheless, there was significant heterogeneity in terms of recovery, with different personal trajectories toward or away from recovery that may require tailored approaches to functional rehabilitation. New psychosocial or policy-based approaches are needed to ensure that more people with schizophrenia experience a long-term course toward both symptom reduction and recovery.Research Trail – Schizophrenia Essay

National Institute of Mental Health grants K23MH077225 and P30MH066248.

Disclosures of Conflict of Interest: D.J. is the Principal Investigator of an National Institute of Mental Health-funded grant for which antipsychotic drugs are donated by AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, and Janssen. None of the other authors have any disclosures of interest to report.Research Trail – Schizophrenia Essay

An essential aspect of research on schizophrenia is ensuring that worthwhile scientific studies are done in a way that does not place vulnerable individuals at unreasonable risk. It is important to educate researchers, advocates, potential participants, reviewers, IRBs, and the general public about ethical principles and controversial issues as they impact research on schizophrenia. Federal regulations mandate IRB consideration of “the special problems of research involving… mentally disabled persons…” (45CFR46.111a3). In recent years, there has been a greater focus on subject monitoring to improve safeguards and minimize risks. The process of informed consent is also going through a process of evolution, in order to help ensure that participants are as aware as possible of key aspects of a study, including risks, benefits, alternatives, purpose and design, etc. We focus here on a few of the issues that are current, are relevant to schizophrenia research, and merit additional empirical study. They include medication discontinuation and placebo control designs, compensation for participation, and capacity to consent.Research Trail – Schizophrenia Essay

research ethics, schizophrenia, placebo, consent capacity
Topic: ethics informed consent institutional review board mentally disabled persons schizophrenia teaching
Issue Section: Special Theme: Empirical and Conceptual Advances in the Ethics of Schizophrenia Research Guest Editors: Laura Weiss Roberts and Laura B. Dunn
Federal regulations (45CFR46.111)1 mandate IRB consideration of “the special problems of research involving … mentally disabled persons …,” and a criterion for IRB approval is that when subjects “are likely to be vulnerable to coercion or undue influence, such as … mentally disabled persons, … additional safeguards have been included in the study to protect the rights and welfare of these subjects.” The Regulations further note (45CFR46.116) that information given to the subject or representative “shall be in language understandable to the subject ….” Beyond that, there is little of specific relevance to schizophrenia research in the “Common Rule” provisions, but naturally there are various interpretations and opinions about how these rules should apply. Some have advocated adding Special Subpart Protections to the Regulations to more specifically cover people with mental disorders, while others have expressed concerns about such efforts. We will be hearing more about this topic in the future, but it will not be a subject of the current discussion.Research Trail – Schizophrenia Essay

An essential aspect of research on schizophrenia is ensuring that worthwhile scientific studies are done in a way that does not place vulnerable individuals at unreasonable risk. It is important to educate researchers, advocates, potential participants, reviewers, IRBs, and the general public about ethical principles and controversial issues as they impact research on schizophrenia. Unfortunately, until recently there has been little effort focused on addressing empirical questions relevant to these issues. The NIH has emphasized the importance of research on ethical issues such as informed consent, and supports an increasing number of studies on such topics.Research Trail – Schizophrenia Essay

In recent years, there has been a greater focus on subject monitoring to improve safeguards and minimize risks. Data and safety monitoring plans are now commonly made explicit in clinical trials, and independent Boards may meet regularly to assess study progress, adverse events, reporting requirements, etc. The process of informed consent is also going through a process of evolution, in order to help ensure that participants are as aware as possible of key aspects of a study, including risks, benefits, alternatives, purpose and design, etc. Below we will focus specifically on a few of the issues that are current, are relevant to schizophrenia research, and merit additional empirical study. They include medication discontinuation and placebo control designs, compensation for participation, and capacity to consent.Research Trail – Schizophrenia Essay

Drug Discontinuation
One especially controversial schizophrenia research design involves either stopping or delaying treatment, often for the purpose of biological studies such as PET scans or neurochemical assays. Delaying treatment,2,3 especially for individuals who have severe disorders (such as schizophrenia), which may benefit from immediate treatment, may create a dilemma. Consent documents now generally include (under “alternatives”) the option to begin treatment immediately, and not to delay or defer (for the purpose of participating in a research study) medication and/or psychotherapy. Individuals must be informed that participation is voluntary and that they can withdraw at any time. They should also know that their symptoms may well worsen, and that suicidal ideation or other dangerous situations may begin to develop. In such situations, they need to know whom to contact.Research Trail – Schizophrenia Essay

Investigators need to set up an adequate safety net to ensure appropriate clinical assessment, and monitoring sufficient to detect and respond to emerging problems. The discontinuation design may be used for selected subject groups who have not benefited substantially from treatment, have experienced problematic side effects, or have chosen (independent of the study) to remain off (or discontinue) treatment.Research Trail – Schizophrenia Essay

Another controversial type of drug discontinuation research involves prolonged discontinuation of effective treatment.4–6 It has been noted that starting patients on medications and leaving them on for many years, adding additional medications as additional symptoms or side effects occur, can create numerous clinical problems. Clearly we would like to know from a scientific perspective, and patients want to know from side effects and other perspectives, how long they “need to take” a given medication or remain in psychotherapy. In many situations, we do not yet know the answers to these questions.Research Trail – Schizophrenia Essay

Unfortunately, discontinuing treatment of people with severe disorders such as schizophrenia may lead to dramatic symptom exacerbations and clinical complications. While it is important to learn how long people need to remain on medications, studies have shown that for many psychiatric disorders like schizophrenia, prolonged treatment is often necessary because of its generally chronic and/or recurring nature. Removal of such treatments naturally will raise some concerns.Research Trail – Schizophrenia Essay

If individuals are being withdrawn from medications to which they are currently responding well, the risks/benefits/alternatives to the discontinuation phase should be made clear in the withdrawal phase consent document. Medication withdrawal protocols may involve substantial risks (relapse, hospitalization, suicidal ideation, or problems at home, school, work, etc). Since these designs are not generally considered to present the prospect of direct benefit (other than diminishing side effects), strong ethical justification is essential. As noted above, selection of subjects who have not benefited from treatment, have had major side effects, or have chosen independently to stop treatment would minimize some of the ethical concerns (but may raise some scientific concerns about generalizability).Research Trail – Schizophrenia Essay

The risk of relapse, consideration of alternative treatments that may be more acceptable, and monitoring safeguards must all be considered by IRBs and investigators, and reflected in consent documents. The selection of potential subjects must be carefully considered, along with the availability of treatment for those who worsen clinically and require rescue medication. One alternative is to remain on a treatment that currently appears to be effective. This might be the case even if the treatment in a clinical trial was a placebo. In fact, continuing individual responders on placebo, and comparing them with responders on active medication, may help determine whether there is a point at which a “separation” occurs; i.e., if the placebo effect seems to diminish over time. This could lead to better empirical data on how long a placebo arm should be continued in various trials.Research Trail – Schizophrenia Essay

Financial Incentives/Compensation
In decades past, it was relatively unusual to pay participants in clinical research, but outlooks have evolved considerably on this subject. For instance, the time of an individual with a mental disorder like schizophrenia is no less valuable than that of anyone else, and compensation is now generally provided to patients if it is to be provided to controls. This was discussed cogently at the December 2001 PRIM&R meeting in Boston. Of course, there are concerns that paying participants large sums of money could be an “undue inducement.” That is, payments should not cause individuals to place themselves at significant risk, which they would not otherwise accept. It has also been pointed out that financial compensation should not be listed in consent documents as a “benefit,” since it is not to be balanced against the risks of a study. We generally want to avoid individuals balancing how much risk of harm to their health they should undertake in order to receive certain compensation. This is especially true given that people with schizophrenia are more likely to be socio-economically disadvantaged.Research Trail – Schizophrenia Essay

Reimbursing individuals for their time, travel, etc., at a reasonable rate is certainly appropriate, and we are seeing this much more commonly today. It has, in fact, been pointed out that there may be an unexpected benefit from reimbursing individuals’ costs related to participation in clinical trials. It has been well demonstrated that individuals in a research protocol, despite being told in the consent process that they are being assigned randomly to a treatment group in a clinical trial, often believe that they are getting what the (research) doctor thinks will help them most. This is the “therapeutic misconception,” which has been described by Paul Appelbaum and colleagues.7 In clinical practice, we do not pay individuals to come in for their appointments or take medications to treat their condition, and some have speculated that such payments during clinical trials may make clearer to participants that this is not individualized treatment. This certainly seems worthy of empirical study. Another interesting question is the extent to which financial compensation may become an undue inducement such that individuals attempt to enter a study denying exclusion criteria, or try to continue in a study despite suffering severe clinical symptoms.Research Trail – Schizophrenia Essay

The above issues are clearly related to the more generic question of why people participate in research in the first place. Certainly schizophrenia and altruism are not mutually exclusive. Many mental disorders are familial, and one should not be surprised that a person wants to help other family members, or society in general, now or in the future. Data have already been gathered by Laura Roberts and others6,8 making clear that altruism (not just possible direct benefit) is an important determinant of research participation. Perhaps some individuals in our society do not believe in altruism and would not participate in a study that did not offer them direct benefit, but to assume that this holds widely for individuals with mental disorders seems completely unwarranted, if not insulting.Research Trail – Schizophrenia Essay

Placebo Controls
Most researchers consider placebo control groups extraordinarily valuable under certain circumstances.9–11 In many cases, we would still be using relatively worthless and/or dangerous treatments had we agreed to abandon studies with placebo arms. If we do not know whether a treatment works, it seems ethically questionable to provide it, especially if it entails problematic side effects. On the other hand, the use of a placebo control needs to be well justified (vs. comparison between experimental and standard treatment arms). Clearly, if permanent or severe progression of disease will occur in the absence of treatment, a placebo control arm is not going to be considered appropriate or justified.Research Trail – Schizophrenia Essay

A related issue is the use of planned debriefing, so that at the end of an acute trial, participants are told what they were receiving and how well their symptoms appeared to respond. Delaying debriefing until the entire study is complete and the blind formally broken may not be considered acceptable by IRBs. In particular, participants who were on placebo are generally offered active treatment after an acute trial.

Debriefing helps people who didn’t respond to a medication avoid that ineffective treatment in the future, and may help them find better alternatives. It also allows those who did respond to seek continuation of the effective treatment, and it is becoming more common for research teams to offer such treatment free of charge (for a period at least as long as the acute trial). To preserve the blind, an independent clinician not part of the research team may conduct the debriefing. After that, there is typically a treatment referral to an available clinician.Research Trail – Schizophrenia Essay

Capacity to Consent
Individuals in a wide variety of situations may have impaired decision-making capacity, for example, at times of great stress. Impaired capacity is not limited to individuals with severe mental disorders like schizophrenia, and such individuals should not be presumed to be decisionally impaired.12 Some research questions may only be answered by research that involves persons with impaired decision-making capacity. Precluding such research could have very negative effects, as the most severely impaired individuals have the greatest need for the benefits of research on etiology and treatment. Limiting research to the least-impaired individuals would hamper research on the underlying causes and potential therapies of schizophrenia. Not all research will directly benefit the individual participant, but it may offer future benefits to others who have or will develop the condition or disorder. For example, genetic studies, biochemical measures, or other “non-therapeutic” approaches may greatly benefit subsequent generations.Research Trail – Schizophrenia Essay

Unlike research involving children, prisoners, pregnant women, and fetuses, no additional Department of Health and Human Services (DHHS) regulations1 specifically govern research involving persons who are cognitively impaired. While limited decision-making capacity should not necessarily prevent participation in research, it is important to keep in mind that additional scrutiny by IRBs and researchers is warranted for research involving this population.Research Trail – Schizophrenia Essay

An individual’s capacities, impairments, wishes, and needs must be taken into account in developing practical and ethical approaches to evaluate their potential participation in clinical studies. Several research groups are developing and testing valid and practical methods to assess capacity to consent, and NIMH will continue to support research addressing these issues. At the May 2005 APA meeting, there were several excellent presentations on this topic. A clear understanding of the implications of various cognitive impairments, along with a careful consideration of proposed clinical research methodology, is needed.Research Trail – Schizophrenia Essay

A “sliding scale” involving assessment of risks, benefits, and capacity to consent should guide the IRB’s decisions regarding additional safeguards. Many strategies are available for investigators as they develop their research protocols, and for IRB members as they evaluate them. In considering increasing levels of risk and/or impairment, investigators should be creative in choosing appropriate protections, seeking strategies used successfully in similar situations.

When reviewing greater than minimal risk research involving individuals with questionable capacity to consent, IRBs should discuss and document the potential value of an independent monitor. A monitor can be appointed to be present when investigators invite individuals with impaired decision-making capacity to participate in a research study. The consent process should be visible throughout, and IRBs have a right to observe recruitment, assessment, the informed consent process, and debriefing of research participants (and/or their family/surrogates).Research Trail – Schizophrenia Essay

Where permitted by law, individuals with impaired capacity may have a family member or other legally authorized representative serve as a surrogate for research decisions, with this role documented during the consent process. Unfortunately, it may be unclear what is permitted by law. Many states have statutes or regulations defining who may serve as surrogates in the context of medical practice, but it is often unclear whether these laws also cover research. OHRP has opined that if a state law permits a certain type of surrogate to authorize a certain type of procedure in the medical practice context, then that same type of surrogate would have authority to authorize similar procedures in the research context.Research Trail – Schizophrenia Essay

Surrogates should be informed of the risks, benefits, and alternatives to the research when they are deciding whether to give permission for an individual to participate. Whenever possible, surrogates should make such decisions based on substituted judgment, reflecting the views of the individual as expressed while decisionally capable. Best interest standards should be used if the values of the individual are not known. It is important that surrogates receive some education about their own role and the cognitive and health status of the research participant, as well as about the study in which the participant may be involved.Research Trail – Schizophrenia Essay

Because informed consent is an ongoing process throughout the course of the protocol, assessing and enhancing comprehension at each stage is essential. Summaries of important information about key elements of a study may be useful, especially when provided on a regular basis, such as at each research assessment/monitoring session. Questions from potential participants and family members should be encouraged, and handouts of frequently asked questions and answers regarding specific human subject protections can be prepared. Communication between members of the research team and participants and their families/surrogates is key to successful research participation.Research Trail – Schizophrenia Essay

There are a great number of ethical questions related to schizophrenia research, and the sooner these are addressed in an empirical manner, the better. Improving consent capacity (and its assessment) is an area of very promising development. We should also acknowledge that many important scientific questions remain unanswered because we cannot yet conduct ethically acceptable studies that will provide valid answers. Advances in research design, and application of basic behavioral and neuroscience findings to the clinical problems of schizophrenia, may greatly improve risk/benefit considerations in such research.Research Trail – Schizophrenia Essay

While the underlying problems of schizophrenia have remained relatively constant over the years, the treatments available, and the clinical problems associated with newer treatments, have changed considerably. Likewise, the basic ethical principles of the Belmont Report13 and the Human Subject Protections Regulations (45CFR46)1 have been in existence for some time, but the way in which these are applied to clinical research issues has also been evolving. The work described in this issue of Schizophrenia Bulletin makes good use of recent interpretations and applications of the science and ethics advances to improve the lives of people with schizophrenia.Research Trail – Schizophrenia Essay