Using animal models for the studies of schizophrenia and depression: The value of translational models for treatment and prevention

Abstract

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

“…For example, adolescent stressed rats show increased anxiety-like behaviours, decreased sociability, cognitive deficits, and increased responsivity to psychostimulants, along with hippocampal hyperactivity, parvalbumin neuron loss, and an overactive dopamine system [ 66 , 67 ]. Such changes are similar to those found in other animal models relevant to schizophrenia [ 88 , 89 ] and consistent with clinical schizophrenia [ 90 ].…”

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

“…Despite the extensive research interest, the understanding of the pharmacological and molecular mechanisms mediating the dysmetabolic effects of antipsychotics is insufficient and incomplete, 4,5 also due to the several confounding factors which are limiting the clinical studies, such as comorbidities and concomitant pharmacological treatment. In this context, preclinical models are irreplaceable research tools, allowing for controlled studies and direct examination of networks and tissues 6 . This is an essential prerequisite for progress, as clinical studies in the vulnerable patient groups in question should rely on sound hypotheses.…”

“…In this regard, a major cause is that modeling of severe psychiatric disorders in animals is inherently challenging. A range of models relying on CNS lesions, pharmacological treatment, genetic deletions, or prenatal exposure have been introduced 6,23 . These models differ in theoretical background and the degree to which they meet validity criteria 24 …”

“…In this context, preclinical models are irreplaceable research tools, allowing for controlled studies and direct examination of networks and tissues. 6 This is an essential prerequisite for progress, as clinical studies in the vulnerable patient groups in question should rely on sound hypotheses. The vast majority of preclinical studies concerning adverse metabolic effects of antipsychotics have been performed in healthy rodents.…”

“…A range of models relying on CNS lesions, pharmacological treatment, genetic deletions, or prenatal exposure have been introduced. 6,23 These models differ in theoretical background and the degree to which they meet validity criteria. 24 The neurodevelopmental methylazoxymethanol acetate (MAM) model is based on prenatal administration of MAM (gestational day 17), which produces a phenotype characterized by persistent, functional, and neuropathological deficits mimicking schizophrenia in adult offspring.…”