for example, hallucinations, delusions, sadness and guilt) cannot be convincingly ascertained in animals. When there are reasonable correlates in animals (for example, abnormal social behavior, motivation, working memory, emotion and executive function), the correspondence may only be approximate.A further complication is determining how symptoms in an animal add up to a recognized human disorder, a seemingly critical issue if the animal is to be used for the development of therapeutics. For the vast majority of pathological states contained in the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM-IVTR) 6 , knowledge of pathophysiology remains scant and objective diagnostic tests are lacking. Consequently, diagnoses are based solely on phenomenology, that is, on symptoms, signs and course of illness (Box 1). As a result, the boundaries between DSM-IVTR disorders and the boundaries between disorder and normal variation are often arbitrary or hazy 7 . This state of affairs creates enormous hurdles for the development and validation of animal models. Investigators and reviewers alike must rely on judgment rather than slavish devotion to meeting all DSM-IVTR criteria for the disorder being modeled.With the exception of some neurodegenerative disorders, DSM-IVTR diagnoses do not currently map onto objectively ascertainable abnormalities of molecules, synapses, cells or neural circuits. For familial Alzheimer's disease, insertion of disease-causing alleles has produced useful rodent models 8,9 that produce amyloid plaques similar to those of human disease. In contrast, for virtually all of the remaining disorders in DSM-IVTR, there are no molecular or cellular abnormalities in the human disease that could validate potential phenomenology in an animal. Instead, reversing the direction of 'validation' , pathology in genetic animal models might usefully be sought in human patients, either in postmortem tissue or via noninvasive imaging 10 . These considerations do not mean that useful animal models are impossible to develop; instead, they suggest that animal models are unlikely to mirror the full extent of a given human neuropsychiatric disorder, especially as currently defined in DSM-IVTR. In addition, individual symptoms observed in animal models may not have a simple, straightforward correspondence to human symptoms. For Neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder and autism are highly prevalent 1 , begin early in life 2 and contribute substantially to disease burden worldwide 3 . Despite the profoundly negative effects of these disorders on public health, progress in understanding their pathophysiology has been frustratingly slow and the discovery of new therapeutic mechanisms is at a near standstill. The molecular targets of current major classes of psychotherapeutic drugs 4 (Supplementary Table ) were all reverse engineered from drugs discovered before 1960 by clinical observation. What factors have impeded progress? Arguably, the most important are the exceedingly challenging neurobiology of higher brain function and the ethical and practical difficulties of examining the living human brain. Although the last two decades have seen rapid progress in the development of noninvasive technologies to study human brain structure and function, there remain substantial limitations in our ability to investigate details of the physiology and molecular biology of the human brain.Given these limitations, it is hard to imagine substantial progress in pathophysiology or therapeutics without good animal models. Unfortunately, current animal models have substantial limitations, ranging from weak validation to poor predictive power for drug efficacy in human disease 5 . As discussed in this review, the generation of convincing and useful animal models of neuropsychiatric disorders represents a major set of challenges that will not have easy answers.
Challenges for producing animal models of mental illness
The increasing ease of developing rodent and invertebrate models by genetic manipulation or other means has not obviated the difficulties of modeling disorders that often seem uniquely human. Many of the symptoms used to establish psychiatric diagnoses in humans