Developing treatments for cognitive deficits in schizophrenia: the challenge of translation

Abstract

Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition.

Keywords: Attention; CNTRICS; MATRICS; reward learning; working memory.

© The Author(s) 2014.

Figures

Figure 1. Representation of the symptoms experienced by patients with schizophrenia

Schizophrenia is a life-long neuropsychiatric disorder in which patients suffer from a variety of symptoms grouped into three types: positive; negative; and cognitive. Positive symptoms are behavioral abnormalities that are present due to the disease, such as auditory and/or visual hallucinations, grandiosity, etc. Negative symptoms are behavioral abnormalities that are diminished due to the disease, such as alogia, anhedonia, affective flattening, and amotivation. Finally, cognitive symptoms are wide-ranging (e.g., reward processing, perception, attention, and working memory) and link most closely to a patient's ability to function in society and can impact the other symptoms. Antipsychotic treatments are only efficacious for positive symptoms. Treating cognitive disruption may however, be key to developing the first truly antischizophrenia medication (Geyer and Gross, 2012).

Figure 2. Schematic of how environmental sensory input is processed through schizophrenia-relevant cognitive processes resulting environmental action

The left panel describes how environmental stimuli are perceived and attentional processes brought to bear through cognitive processes until decisions are made and action is taken. This process is detailed in the right panel which also includes paradigms with cross-species relevance to that cognitive domain. As stimuli are perceived, knowledge of relevance/irrelevance of these stimuli enables attending to currently appropriate stimuli. Knowledge of relevant and irrelevant stimuli may be located in either working or long-term memory (indicated by dashed arrow). Because the 5C-CPT and SAT contain relevant and irrelevant stimuli, these tasks measure attention consistent with the CPTs used in humans which includes responding to relevant and irrelevant information. The 5CSRTT measures sustained attention to relevant information. Attention to external stimuli enables information to enter working memory. Working memory is another multi-faceted process which has subsystems of span capacity and maintenance of information which are held online for the manipulation of that information. As is clear, while span capacity (OST & RAM) and maintenance of information (DDM) can be measured in animals, the manipulation of information and working memory cannot. Working memory is important however, for associative learning leading to long-term memory, planning, adaptation, and decision making. Associative learning enables information to enter long-term memory and can be measured using the ASST, PLT, and TI tasks. Long-term memory can also be measured using tasks like the MWM and TI task. Adaptation to changing rules in the environment can be measured using the ASST and PRLT. Working memory, long-term memory, and adaptation, all contribute to planning, another behavior that has yet to be measured in rodents due to its internal nature. Inhibitory control is important for non-responses to irrelevant stimuli as well as adaptation to the environment and decision making. Inhibition of responding to irrelevant stimuli can be measured using the 5C-CPT or go-nogo tasks, while inhibitory processes to initiated behaviors can be measured using the SSRT. Decision making is the final process incorporating aspects of working memory, planning, and adaptation. Decision making can be inferred from changing behaviors to reward or punishment during learning, e.g., IGT, PLT, and PRLT. Finally, the motivation or the perceived reward value of the stimuli also contribute to the degree these cognitive processes are engaged. The properties of these behaviors can be measured using PRB studies, PLT, and bias in response to reward probabilities.

Figure 2. Schematic of how environmental sensory input is processed through schizophrenia-relevant cognitive processes resulting environmental action

The left panel describes how environmental stimuli are perceived and attentional processes brought to bear through cognitive processes until decisions are made and action is taken. This process is detailed in the right panel which also includes paradigms with cross-species relevance to that cognitive domain. As stimuli are perceived, knowledge of relevance/irrelevance of these stimuli enables attending to currently appropriate stimuli. Knowledge of relevant and irrelevant stimuli may be located in either working or long-term memory (indicated by dashed arrow). Because the 5C-CPT and SAT contain relevant and irrelevant stimuli, these tasks measure attention consistent with the CPTs used in humans which includes responding to relevant and irrelevant information. The 5CSRTT measures sustained attention to relevant information. Attention to external stimuli enables information to enter working memory. Working memory is another multi-faceted process which has subsystems of span capacity and maintenance of information which are held online for the manipulation of that information. As is clear, while span capacity (OST & RAM) and maintenance of information (DDM) can be measured in animals, the manipulation of information and working memory cannot. Working memory is important however, for associative learning leading to long-term memory, planning, adaptation, and decision making. Associative learning enables information to enter long-term memory and can be measured using the ASST, PLT, and TI tasks. Long-term memory can also be measured using tasks like the MWM and TI task. Adaptation to changing rules in the environment can be measured using the ASST and PRLT. Working memory, long-term memory, and adaptation, all contribute to planning, another behavior that has yet to be measured in rodents due to its internal nature. Inhibitory control is important for non-responses to irrelevant stimuli as well as adaptation to the environment and decision making. Inhibition of responding to irrelevant stimuli can be measured using the 5C-CPT or go-nogo tasks, while inhibitory processes to initiated behaviors can be measured using the SSRT. Decision making is the final process incorporating aspects of working memory, planning, and adaptation. Decision making can be inferred from changing behaviors to reward or punishment during learning, e.g., IGT, PLT, and PRLT. Finally, the motivation or the perceived reward value of the stimuli also contribute to the degree these cognitive processes are engaged. The properties of these behaviors can be measured using PRB studies, PLT, and bias in response to reward probabilities.