Molecular Psychiatry (2007) 12, 904–922 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp FEATURE REVIEW The pipeline and future of drug development in schizophrenia JA Gray1 and BL Roth2 1Department of Psychiatry, University of California, San Francisco, CA, USA and 2Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia. Molecular Psychiatry (2007) 12, 904–922; doi:10.1038/sj.mp.4002062; published online 31 July 2007 Keywords: antipsychotics; cognition; negative symptoms; drug discovery; preclinical models; target validation Introduction antipsychotic drugs. Clozapine itself has become the ‘gold standard’ antipsychotic medication because Since the discovery of the antipsychotic effect of of its absence of debilitating extrapyramidal side chlorpromazine more than 50 years ago,1 the number effects and its demonstrated clinical superiority in of antipsychotic medications available for the treat- treatment-resistant schizophrenia3 and suicidality.4 ment of schizophrenia has tremendously increased. Whether clozapine has any significant beneficial With the development of the first-generation anti- effect on negative symptoms and cognition is un- psychotics, or typical antipsychotics, it was for the clear.2,5 Clozapine, however, is associated with its first time possible to treat the ‘positive’ symptoms of own set of serious side effects including weight gain, schizophrenia, such as delusions and hallucinations, diabetes and an increased risk of seizures and leading to the deinstitutionalization of the world’s agranulocytosis.6 mentally ill. The typical antipsychotic drugs, how- The documented superiority of clozapine3,7 over ever, are generally not thought to be effective at other antipsychotic drugs has led to an intense effort treating the ‘negative’ symptoms, such as anhedonia over the past 15–20 years to develop clozapine-like and lack of motivation, and cognitive dysfunction of atypical antipsychotics that are safer and better schizophrenia and have a high burden of extra- tolerated than clozapine. As such, multiple atypical pyramidal side effects (EPS).2 and pseudo-atypical antipsychotic drugs, including The reintroduction of clozapine in the United risperidone, olanzapine, quetiapine and ziprasidone States in 1989, issued in the current era of atypical have been developed. Expectations that these agents or second-generation antipsychotics. Atypical anti- comprised a breakthrough in the treatment of schizo- psychotic drugs are differentiated from typical anti- phrenia, especially with regards to improvements in psychotic drugs by virtue of a relative lack of EPS and negative symptoms and cognition were initially high.8 serum prolactin elevation as compared with typical These expectations, however, have not been rea- lized.9,10 While there is evidence that most of the Correspondence: Dr JA Gray, Department of Psychiatry, Univer- new medications offer, at best, modest advantages sity of California, San Francisco, 401 Parnassus Ave, Box R-0984, over the typical antipsychotic drugs with regard to San Francisco, CA 94143-0984, USA. E-mail: [email protected] improvement in negative symptoms, cognitive im- Received 29 March 2007; revised 20 May 2007; accepted 24 May pairment and functional capacity, the improvements 2007; published online 31 July 2007 are not consistent among studies.2,11,12 In addition, the The drug discovery pipeline in schizophrenia JA Gray and BL Roth 905 atypical antipsychotics carry their own substantial is grounded in the complexity of schizophrenia which side-effect burden, specifically weight gain and the is characterized by severe and variable symptoms in a metabolic syndrome.13,14 number of symptom domains, including positive While the introduction of antipsychotic medica- symptoms such as hallucinations, delusions, and tions has had a profound effect on the treatment of disorganized thought, negative symptoms such as a schizophrenia over the past 50 years, and the atypical lack of motivation and interest, and a blunted affective antipsychotic drugs have provided a larger and more range, and symptoms of cognitive impairments in diverse armamentarium of treatment options, the attention, working memory, and a variety of executive advances that have been made since the discovery functions. All of the currently approved drugs for the of the antipsychotic properties of chlorpromazine treatment of schizophrenia, however, were developed have been small and incremental. Thus, enormous and are most efficacious at treating the positive challenges remain in the long-term treatment of this symptoms of the disease while the negative symptoms debilitating disease and continuing with the current and cognitive impairments actually contribute dis- paradigms of drug discovery is unlikely to produce proportionately more to the long-term disability in significant advances.15,16 It is therefore important to patients with schizophrenia.21 continue to pursue diverse molecular targets for It is clear that patients who exhibit significant discovering new antipsychotic compounds and to negative symptoms have particularly poor functional devise novel paradigms for drug discovery in schizo- capacity and quality of life22,23 and while there was phrenia. optimism that the atypicals comprised a breakthrough A fundamental barrier to the discovery and devel- in the treatment of negative symptoms,8 this prospect opment of novel treatments for schizophrenia remains has not been realized to a clinically significant that our level of understanding of the biological degree.9,10 Despite the limitations of current medica- processes involved in schizophrenia is not sufficient tions and the morbidity associated with negative to predict the therapeutic value of novel drug symptoms, no drug has received Food and Drug targets.16 Thus, unvalidated targets are frequently left Administration (FDA) approval for an indication of unpursued by the pharmaceutical industry and, negative symptoms. As such, the National Institutes frequently, companies have focused on alterations of of Mental Health (NIMH) has recently released a existing medications (that is, separating enantiomers consensus statement on the negative symptoms of or marketing active metabolites; for example 9-OH- schizophrenia24 highlighting that negative symptoms risperidone or paliperidone),17 finding additional represent a distinct and clinically important entity compounds that hit known and validated targets that should be a focus of future drug development (‘me too’ drugs; for example ORG-5222 or asena- efforts. pine),18 and on gaining approval on new indications In addition to negative symptoms, schizophrenia is for already marketed drugs19 (for example clozapine also characterized by significant cognitive impair- for suicide in schizophrenia4). These methods, how- ments. For example, patients with schizophrenia ever, cannot continue indefinitely as the number of have been documented to have problems with such possibilities is limited and thus it is critical to attention, working memory and learning and a variety find new approaches to drug development. Interest- of executive-level functions including abstract think- ingly, many of the atypicals will soon be going off ing and problem solving.25,26 Indeed, a meta-analysis patent, beginning with the launch of generic risper- of cognitive deficits suggested that indices of cogni- idone in 2007. Thus, there is significant interest and tive deficits are much better predictors of functional urgency within the pharmaceutical industry and outcome than indices from any other symptom among schizophrenia basic scientists and clinicians domain.27 However, these cognitive deficits have in developing safer and more-effective treatments for been relatively unimproved by currently approved schizophrenia. antipsychotic drugs, though some evidence exists for In this review we will briefly discuss the current the superiority of atypicals such as olanzapine and pipeline of drugs for schizophrenia (Table 1) and will risperidone over typicals.5,28,29 Owing to the remain- outline many of the strategies and targets currently ing need for improved treatment