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Where now for schizophrenia research? David J Nutt, Anna C. Need
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Received date: 31 March 2014 Revised date: 17 May 2014 Accepted date: 19 May 2014 Cite this article as: David J Nutt, Anna C. Need, Where now for schizophrenia research?, European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2014.05.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Where now for schizophrenia research? David J Nutt1 Edmond J Safra Prof of Neuropsychopharmacology and Anna C. Need Lecturer in Neurogenetics Division of Brain Sciences Imperial College London 1 Email: [email protected]
Schizophrenia continues to pose a serious challenge to neuroscience and psychiatry as well as to health care systems and to the patients and families who suffer this terrible and disabling illness. Major developments in the past few months in both genetics and drug development oblige us to consider novel drug discovery tactics for future schizophrenia research. Here we review what we consider to be the key issues and some suggested solutions.
Keywords Schizophrenia; Genetics; Serendipity; Glutamate; Clozapine; Antipsychotics Death by a thousand variants: how genetics has fundamentally altered our understanding of schizophrenia In October, Nature Genetics published the results of the latest genome‐wide association study (GWAS) of schizophrenia with close to 60,000 probands and controls (Ripke et al. 2013). No common genetic variant that contributed any meaningful effect was found, nor has anyone expected to find such a variant since the first phase of schizophrenia GWAS were published several years ago (Need et al., 2009; Purcell et al., 2009; Shi et al., 2009; Stefansson et al., 2009) The authors found 22 independent genetic loci that weakly but significantly associated with schizophrenia and used these data to calculate that around 8,000 independent SNPs may collectively be able to explain about half of the genetic contribution to schizophrenia. The remaining hope for GWAS is that some of these thousands of SNPs will implicate genes that converge on a few specific and informative pathways. Convergence on informative pathways is now the residual ambition for schizophrenia sequencing studies as well. An early exome sequencing study ruled out a large contribution from genetic variants of intermediate frequency (Need et al., 2012) , but left open the possibility that a modest number of genes could be important. This hope was just dampened by two much bigger exome sequencing studies published in Nature that failed to find significance support for any individual genes (Fromer et al., 2014; Purcell et al., 2014). Although sequencing studies involving tens of thousands of schizophrenia patients will (hopefully) begin to implicate individual genes, they will each be relevant to only a very small fraction of schizophrenia cases. From an etiological point of view, these studies showed an exciting convergence: all three showed a suggestive enrichment of signals from calcium channel genes and both exome sequencing studies implicate the postsynaptic ARC complex. Unfortunately, while these pathways include tractable drug targets, their ubiquity in the brain means that they are not likely to lead to drugs that are selective for schizophrenia. Indeed, calcium channels have also been implicated by genetic studies of bipolar disorder (Ferreira et al., 2008) and there is some evidence that the calcium channel blocker verapamil may be effective as an add‐on treatment resistant bipolar disorder (Mallinger et. al., 2008). However calcium channels have critical roles in the developing brain and since prevention of schizophrenia may need early pre‐puberty interventions, effective drugs for schizophrenia based on calcium channel antagonism may prove impossible to develop with an acceptable safety margin. There are some other important aspects of these findings. For example some of the most exciting earlier “discoveries” of genes for schizophrenia such as dysbindin and neuregulin (Owen et al., 2005) have not replicated in larger studies, and there is no evidence that variation in genes in the dopamine system (including the infamous COMT) have any role in
schizophrenia. This is a real paradox given that the only drugs that work in the disease are those that block dopamine D2 receptor (DRD2) actions (Kapur and Mamo, 2003). Additionally, where genetic variants have reliably been associated with schizophrenia, either through analysis of copy number variants (CNVs) or very large GWAS, they have indicated a shared genetic etiology across a wide range of brain disorders including schizophrenia, ADHD, bipolar disorder, autism, intellectual disability(Cross‐Disorder Group of the Psychiatric Genomics et al., 2013; Grayton et al., 2012). The end of the age of glutamate? The second recent disappointment in schizophrenia research is the failure of the two phase 3 trials of bitopertin (Grogan, 2014). This is a Roche drug that works to enhance the function of the excitatory neurotransmitter glutamate at the NMDA receptor. A body of preclinical and human postmortem studies have implicated deficient glutamate function, particularly in the prefrontal cortex in aspects of schizophrenia, especially cognition and negative symptoms. Glutamate is far too activating a neurotransmitter to be directly mimicked or potentiated in the brain as anxiety and then seizures are produced. To overcome this obstacle allosteric modulators such as bitopertin and organon 25935 (Christmas et al., 2014) have been developed that more subtly increase glutamate receptor function by increasing the availability of glycine in the synaptic cleft. As glycine is a glutamate potentiator, more glycine means more efficacy of glutamate at the NMDA receptor. Glycine reuptake blockers are safe in humans and a phase 2 trial of bitopertin showed promise as an add‐on in schizophrenia (Stein, 2012). However the failure of the two phase 3 regulatory trials almost certainly means that this drug will not now become a medicine. Moreover, the failure of this major body of work, coupled with the fact that drugs working on other glutamate receptors such as the Lilly metabotropic receptor agonist pomaglumetad methionil (Heimer, 2012) have also failed to show efficacy in phase 3 studies after promising phase 2 results, is likely to have a very deleterious effect on the confidence of other pharmaceutical companies to stay in – let alone enter – this field. Given the highly significant pull out from the psychiatry sector in recent years (Nutt and Goodwin, 2011) this could mark the death‐knell for pharmaceutical investment in new treatments for psychiatric disorders. The bitopertin story shows that developing new drugs based on a theory is very risky. This issue of target specificity in brain drug development is the leading challenge to this field today and the source of great hubris to the neuroscientific field. In the past 30 years there has not been a single drug developed based on a new theory of psychopharmacology; indeed one could argue that in the whole history of psychiatry there have been no conceptual treatment breakthroughs based on neuroscience insights. The drugs we have today are all refinements of those discovered in the 1950s by serendipity. Wherever drug targeting tests a theory it has failed. Another major example other than the glutamate drugs in schizophrenia has been the failure of amyloid‐reducing drugs e.g. bapineuzumab, in Alzheimer's disease (Wasilewski and Rose, 2012). How to remedy the situation? There are many exciting possible directions for developing new schizophrenia treatments but we must be carefully guided by our past successes and failures. There are two unequivocal successes in schizophrenia treatment – that dopamine D2 receptor blocking drugs are effective for some symptoms in a proportion of patients and that clozapine has special efficacy in the more severely ill, treatment resistant patients (Kane et al., 1988). Both facts were discovered by serendipity. The dopamine receptor blocking discovery has been
successfully utilized but may offer more (Schmidt et. al. (2012), clozapine has proved impossible to improve on largely because its special properties are still not understood. Improve current medications Given the apparent genetic heterogeneity of schizophrenia, it is very unlikely that one drug will fix all. Indeed it is remarkable that any drugs can be shown to work on as many people as they do! Dopamine receptor blocking drugs help a significant proportion of patients particularly those with positive symptoms [delusions and hallucinations] and when used with high quality family psychotherapy input can produce very enduring good outcomes (Leff et al., 1982). However they don't work in everyone, possibly because not all patients with schizophrenia have a dopamine related illness. For instance, a small subgroup of schizophrenics may have undiagnosed rare diseases such as limbic encephalitis (Martinez‐ Martinez et. al. 2013). One simple option for improvement in schizophrenia treatment would be to stratify patients using biomarkers that predict drug response. Very encouragingly, a genetic variant was recently identified that very effectively predicts response to lithium in Chinese bipolar patients (Chen et al., 2014). To date, however we have failed to find clinically useful genetic predictors of antipsychotic response in schizophrenia, despite intense research effort. Current evidence from radioimaging studies reveals a subset of schizophrenia patients that have excessive dopamine release to stimulants (Laruelle et al., 1996) or increased dopamine turnover (Fusar‐Poli and Meyer‐Lindenberg, 2013) Cheap and reliable markers of those patients where symptoms are caused by brain dopamine excess could help direct interventions – and those that do not show this should be the prime group in which new treatments should be targeted. Improving dopamine blockers is another tractable approach, since we know what systems we are working with. All current antipsychotics have adverse effects and refining medications to minimise these should be encouraged. This should include development of dopamine blockers with different profiles at other receptor systems e.g. noradrenaline receptors (Litman et al., 1996) and new partial agonists that may improve on the only current one, aripiprazole. Drugs that target the enhanced presynaptic dopamine function seen in some patients, particularly in the prodrome, need to be considered. Here I (DJN) am reminded of a patient seen many years ago whose schizophrenia symptoms improved remarkably for weeks after he had taken a deliberate overdose of his antihypertensive medication L‐methyl‐DOPA [Aldomet]. We presumed that this had effectively depleted his synaptic pool of dopamine for a while, and regret now never writing it up. Would a trial of this be warranted? A moonshot for clozapine? The failure of current science to explain the unique mechanism of action of clozapine is one of the most humbling aspects of the current situation. Hundreds of millions of dollars have been spent by pharmaceutical companies and government research agencies on this problem with no conclusive outcomes. Most companies have now given up the search as they pull out of brain research altogether, and those that are left have much reduced investment. However we know there must be a solution, so how to find it? An integrated network of researchers spanning all aspects of neuroscience and clinical research will be required, just as that which underpinned the successful moonshots. In recent years we have seen specific investments by both Europe and the USA in brain research in an attempt to make significant breakthroughs in conceptual understanding [Human Brain Project
https://www.humanbrainproject.eu/en_GB]. The economic and human rewards offered by cracking the clozapine question could be as great and should be more tractable since the question is more limited. Back to the future? Can we go back to the future and actively seek serendipity? All the current drug classes we use in psychiatry were discovered by astute clinical observation of unexpected effects of drugs used to treat other disorders. In the case of schizophrenia, chlorpromazine was found by testing – in patients – of new sedative drugs. It took more than 5 years for its mode of action (dopamine blockade) to be discovered. Recently another potential treatment for schizophrenia has been similarly found by accident. This is minocycline, an old antibiotic that showed remarkable effects on schizophrenia symptoms in two Japanese patients given it for life threatening infections (Dean et al., 2012). Since then there have been several trials of it as an add‐on to antipsychotic treatments and results have been quite promising (Chaudhry et al., 2012). We now need to work out why minocycline works. It may be that some patients with schizophrenia have latent infections but this seems unlikely. Minocycline has effects a range of effects on microglia, glutamate systems and on neuroinflammation any of which might be significant (Dean et al., 2012). The use of serendipity to discover potential treatments needs to be encouraged. Although well‐established processes for declaring adverse effects of drugs exist, the same is not true for the reporting of beneficial effects. Traditionally this would have occurred as case reports but many journals have now eliminated these as they reduce their impact factor. So new avenues for reporting such cases need to be developed. Case reports may be difficult to publish in journals, but a publically accessible web page could be used to rapidly report and disseminate suspected antipsychotic, antidepressant or anxiolytic effects of existing drugs, just as they are for one‐off associations of genetic variants with disease (e.g., Decipher http://decipher.sanger.ac.uk/). Such potential new therapeutic insights are unlikely to be taken up by the pharmaceutical companies so other approaches are required. Such studies could be modeled on the open label ones such as those of Delay and Deniker (1952) and Kuhn (1958) that identified the special properties of chlorpromazine and imipramine i.e. in small well defined patient cohorts. National or international networks to allow this should be set up and funded. Also such expert centres would also allow the training of the next generation of clinical researchers. Serendipity also can exist at the preclinical level. Some drugs for other indications might have some impact in brain disorders, particularly intracellular targets such as enzymes and inflammatory modulators. However modern pharmaceutical research processes are very focused on single diseases, and this usually precludes these compounds being tested in models of brain function. Indeed many pharmaceutical companies now have no interest or in‐house expertise in brain pharmacology at all. If these drugs make it to the clinic then they can be tested by others but if they do not then they usually become extinct, a lamentable loss of scientific knowledge and opportunity (Nutt et al., 2014). At the very least these compounds should be put into the public domain as soon as possible after they cease to be of commercial value. Can genetics rise from the ashes? It is clear that the genetics of schizophrenia is not going to be simple, and most findings will not be rapidly clinically applicable, if at all. However there may be some exceptions. There
are currently several groups and consortia that are whole‐genome sequencing very large numbers of schizophrenia patients, and we can expect one, and hope for a second, important outcome. The first is that some patients will have causal mutations in genes that are already drug targets, and these patients may respond to already approved treatments that would never have been trialed for schizophrenia patients otherwise. The second outcome, that many are pinning their hopes on, is that a ‘new DRD2’ will be discovered. This is not of course a literal hope for a new dopamine receptor, rather that associated genes will begin to converge on an unexpected molecular pathway, which can be targeted either with new or existing medications. Improving back translation The relevance of mutant mouse models may seem to be diminished if any schizophrenia‐ associated genetic variant either has only a miniscule additive effect on risk, or is seen only in one or a few patients. Certainly the hope that a mutant mouse could faithfully reproduce human psychiatric disorders has always been an exercise more of faith than certainty; mouse brains are significantly different in size and cortical structure, and schizophrenia diagnosis is based on reports of symptoms that would be impossible to measure in mice even if they could be recreated. Mouse genetic models may nevertheless play a part in the identification of schizophrenia genes and their subsequent guidance for treatments. With sample sizes in the tens or hundreds of thousands, it is very likely that some genes will be statistically demonstrated to have very highly penetrant schizophrenia associated genetic variants. However, there will be many more genes that are not mutated in enough patients to reach this threshold. With novel technologies such as CRISPR (Terns and Terns, 2014), we can introduce known schizophrenia‐associated mutations in mice and look at their effects on other gene products. Genes or gene products that are explicitly affected by known schizophrenia‐associated mutations may have damaging mutations in other patients, and these can be prioritized for targeted sequencing studies in larger cohorts, expanding the list of definitively associated genes. Similarly, such mouse models can be used to reveal novel molecular pathways that schizophrenia mutations are converging on, and potentially identify our hypothetical ‘new DRD2’ (Kapur and Mamo, 2003). Mice (and rats) can also help us without being mutated. The dopamine blocking actions of chlorpromazine were discovered using simple pharmacological challenge tests in rodents. Dopamine was enhanced by giving the precursor L‐dopa and a releaser amphetamine, and the subsequent behavioural activation was blocked by chlorpromazine. All other antipsychotics were validated with the same assays. Such a simple screen allows us to test many thousands of new compounds for the ability to decrease dopamine hyperactivity. Some of these might work through novel mechanisms i.e. other than by direct receptor blockade, and could offer new approaches to treatment. Encourage symptom targeting If we can’t treat the disease of schizophrenia then at least we can help reduce symptoms. This is what antipsychotics do; they block dopamine D2 receptors and this somehow reduces positive symptoms, possibly by altering the perceived salience of sensory inputs (Kapur, 2003). However, there are many other symptoms in schizophrenia with cognitive and motivational problems being prominent, and indeed the major cause of disability. It is becoming accepted by regulatory bodies that approaching these with medicines is an acceptable way to progress, though none has yet been licensed. The challenges and
methodologies for this approach to cognition in schizophrenia has recently been the subject of a major consensus meeting (Nutt et al., 2013). Similar approaches to negative symptoms are being developed e.g. the use of amphetamines to enhance motivation and reduce negative symptoms in patients treated with antipsychotics (to prevent the positive symptoms worsening) (Lasser et al., 2013). Look into the brain Another approach that has been much touted is that of measuring brain processes, particularly with imaging, to identify schizophrenia‐associated neural features, and then trying to remedy them with new treatments. Such neural features are known as ‘endophenotypes’ and are also present in unaffected family members, who can be more easily studied without the confounding effects of antipsychotic treatments. The traditional theory of endophenotypes is based on a threshold model, in which multiple genetic variants contribute to schizophrenia in an additive manner (Gottesman and Gould, 2003). Close relatives are assumed to have many of the disease‐associated alleles, but not enough to push them over the edge into disease. However, in recent years it has been discovered that some schizophrenia patients have single genetic variants that have a very strong effect on disease risk, and thus do not adhere to the threshold model. Despite their strong effects, in some cases these variants are inherited from parents or carried by siblings that do not have schizophrenia. These unaffected carriers can have abnormalities similar to their patient relatives that could be explored for drug response (Spence et al., 2000). Of course the fact that they do not have schizophrenia means that in some (as yet unknown) ways their brains are different and the effect of this may interfere with the results of the drug testing. Humans, too, can be useful without being mutated. As for mice, aspects of schizophrenia can be modeled in normal healthy volunteers by giving them drugs that profoundly alter their brain such as psychedelics, cannabis or ketamine (Carhart‐Harris et al., 2013). The challenge here is to find medicines that block the effects of these drug challenges without directly interfering with the challenges pharmacology. So atypical antipsychotics will block the effects of psychedelics just because they block the 5HT2A receptors to which psychedelics bind. Interesting new developments here include the use of MRI measures of brain connectivity that are disrupted by drugs such as psychedelics and ketamine in a similar fashion to that seen in schizophrenia (Carhart‐Harris et al., 2012). New agents e.g. a tyrosine‐kinase inhibitor, are currently being tested in this model of schizophrenia (MRC/AstraZeneca: Mechanisms of Disease Call assets, http://www.mrc.ac.uk/Fundingopportunities/Calls/MoD/compounds/index.htm) and if these work in the lab – and then are validated in the clinic – this may prove a useful way forward. Conclusions Schizophrenia remains a common and very damaging brain disease that presents a serious challenge to neuroscience and clinical therapeutics. The hoped‐for advances that the genetic revolution offered have not yet materialized, and we remain, as ever, looking for answers that seem to lie just round the next technological corner. Moreover, treatment advances based on neuropathology and animal models of glutamate dysfunction have also failed. We need now to digest the implications of these disheartening findings and develop new research strategies that will give succor to research funders as well as the pharmaceutical industry and give hope to patients and their families.
Some of these will involve more pragmatic and “mundane” research and less‐theory based approaches, and the funding of these will require some changes in the way research is viewed by funding agencies. Also structural funding sources could be used for setting up research centres instead of for example new roads. Others require the international pooling of insights and data on the drugs that do work, particularly clozapine, to develop newer safer alternatives. For this to work there needs to be widespread buy‐in from funders, regulators and scientists. Dedicated funds to support serendipity might be made available e.g. to collect data of positive but unexpected effects on schizophrenia and related syndromes induced by other medicines (see the recent report that warfarin might reduce symptoms http://www.medscape.com/viewarticle/825210). These could be run alongside national databases that collect information on the adverse effects of medicines. References Carhart‐Harris R, Brugger S, Nutt D, Stone J (2013) Psychiatry's next top model: cause for a re‐think on drug models of psychosis and other psychiatric disorders. J Psychopharmacol. 2013 Jun 19. [Epub ahead of print] PMID: 23904408. Carhart‐Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Hobden P, Evans J, Sharp DJ, Feilding A, Wise RG, Nutt DJ (2012) Imaging the brain mechanisms of disturbed ego‐ boundaries following psilocybin: a model for prodromal psychosis? Schizophrenia Bulletin 39(6):1343‐51. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn, G, Deakin B (2012) Minocycline benefits negative symptoms in early schizophrenia: a randomised double‐blind placebo‐controlled clinical trial in patients on standard treatment J Psychopharmacol September 2012 vol. 26 no. 9 1185‐1193 doi: 10.1177/0269881112444941. Chen CH, Lee CS, Lee MT, et al. (2014) Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med Jan 9 2014;370(2):119‐128. Christmas D, Alison Diaper A, Wilson S, Rich A, Phillips S, Udo de Haes J, Sjogren M, Nutt DJ (2014). A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers. Human Psychopharmacology Jan 14. doi: 10.1002/hup.2384. [Epub ahead of print]. Cross‐Disorder Group of the Psychiatric Genomics, et al. (2008) Collaborative genome‐wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40, 1056‐1058. Dean OM, Data‐Franco J, Giorlando F, Berk M (2012) Minocycline CNS Drugs: 5:391‐401. Delay J, Deniker P. (1952) Le traitement des psychoses par une me´thode neurolytique de´rive´e de l’hibernothe´rapie. (le 4560 R.P. utilise´ seul en cure prolonge´e et continue.) CR Congre`s Me´d Alie´n Neurol (France) 1952;50:497–502. Ferreira, MA, O'Donovan, MC, Meng, YA, et. al. (2008) Collaborative genome‐wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40, 1056‐1058.
Fromer M, Pocklington AJ, Kavanagh DH, et al. (2014) De novo mutations in schizophrenia implicate synaptic networks. Nature Feb 13 2014;506(7487):179‐184. Fusar‐Poli P, Meyer‐Lindenberg A (2013) Striatal presynaptic dopamine in schizophrenia, Part II: meta‐analysis of [18F/11C]‐DOPA PET studies ‐ Schizophrenia bulletin, 2013. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry Apr 2003;160(4):636‐645. Grayton HM, Fernandes C, Rujescu D, and Collier DA (2012) Copy number variations in neurodevelopmental disorders. Prog. Neurobiol. 99: 81‐91 Grogan K (2014) Setback for Roche schizophrenia drug bitopertin. PharmaTimes online. Available at: http://www.pharmatimes.com/article/14‐01‐ 21/Setback_for_Roche_schizophrenia_drug_bitopertin.aspx . Accessed on March 20, 2014. Heimer H (2012) News Brief—Dead End for Lilly mGluR Schizophrenia Drug. Schizophrenia Research Forum. Available at: http://www.schizophreniaforum.org/new/detail.asp?id=1797 . Accessed on March 20, 2014. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the Treatment‐Resistant Schizophrenic: A Double‐blind Comparison With Chlorpromazine Arch Gen Psychiatry 45(9):789‐796. doi:10.1001/archpsyc.1988.01800330013001. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry 160:13‐23. doi:10.1176/appi.ajp.160.1.13. Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progress in Neuro‐Psychopharmacology and Biological Psychiatry Volume 27, Issue 7, October 2003, Pages 1081–1090. KUHN R. (1958) The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958 Nov;115(5):459‐64. PubMed PMID: 13583250. Laruelle M, Abi‐Dhargham A, Van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbii SS, Baldwin RM, Seibyli JP, Krystal JH, Charney Down's Syndrome , Innis RB. (1996) Single photon emission computerized tomography imaging of amphetamine‐induced dopamine release in drug‐free schizophrenic subjects. Proc. Natl.Acad. Sci. USA Vol. 93, pp. 9235‐9240, August 1996 Neurobiology. Lasser RA, Dirks B, Nasrallah H, Kirsch C, Gao J, Michael L Pucci ML, Knesevich MA, Lindenmayer J‐P (2013) Adjunctive Lisdexamfetamine Dimesylate Therapy in Adult Outpatients With Predominant Negative Symptoms of Schizophrenia: Open‐Label and Randomized‐Withdrawal Phases. Neuropsychopharmacology (2013) 38, 2140–2149; doi:10.1038/npp.2013.111; published online 12 June 2013. Leff J, Kuipers L, R Berkowitz R, Eberlein‐Vries R, Sturgeon D. [1982] A controlled trial of social intervention in the families of schizophrenic patients. The British Journal of Psychiatry (1982) 141: 121‐134 doi: 10.1192/bjp.141.2.121.
Litman RE, Su TP, Potter WZ, Hong WW and Pickar D (1996) Idazoxan and response to typical neuroleptics in treatment‐resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Brit J Psychiatry 1996, 168:571‐579. DOI: 10.1192/bjp.168.5.571. Mallinger AG, Thase ME, Haskett R, Buttenfield J, Luckenbaugh DA, Frank E, Kupfer DJ, Manji HK. (2008) Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.Bipolar Disord. Dec;10(8):856‐66. doi: 10.1111/j.1399‐5618.2008.00636.x. Martinez‐Martinez P1, Molenaar PC, Losen M, Stevens J, Baets MH, Szoke A, Honnorat J, Tamouza R, Leboyer M, Os JV, Rutten BP. (2013) Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders. Front Genet. Sep 20;4:181. eCollection 2013. Need AC, Ge D, Weale ME, et al. (2009) A genome‐wide investigation of SNPs and CNVs in schizophrenia. PLoS genetics Feb 2009;5(2):e1000373. Need AC, McEvoy JP, Gennarelli M, et al. (2012) Exome sequencing followed by large‐scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet Aug 10 2012;91(2):303‐312. Nutt D, Gispen‐de Wied CC, Arango C, Keefe RS, Penadés R, Murphy DG, Robbins TW, Sahakian BJ (2013) Cognition in schizophrenia: Summary Nice Consultation Meeting 2012. Eur Neuropsychopharmacol. May 15. pii: S0924‐977X(13)00100‐4. doi: 10.1016/j.euroneuro.2013.03.005. Nutt D, Goodwin G. (2011) ECNP Summit on the future of CNS drug research in Europe 2011: report prepared for ECNP by David Nutt and Guy Goodwin. Eur Neuropsychopharmacol. 21(7):495‐9. PMID: 21684455. Nutt DJ, Hayes A, Kilpatrick G (2014) The extinction of drugs for clinical research: can the ECNP Medicines Chest save them? European Neuropsychopharmacology ‐ in press. Spence SA, Grasby PM, Liddle PF (2000) Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk Focal dysfunction and distributed disconnectivity reappraised The British Journal of Psychiatry (2000) 176: 52‐60 doi: 10.1192/bjp.176.1.5. Owen MJ, Craddock N, O'Donovan MC. (2005) Schizophrenia: genes at last? Trends Genet Sep 2005;21(9):518‐525. Purcell SM, Moran JL, Fromer M, et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature Feb 13 2014;506(7487):185‐190. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature Aug 6 2009;460(7256):748‐752. Ripke S, O'Dushlaine C, Chambert K, et al. (2013) Genome‐wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet Aug 25 2013.
Shi J, Levinson DF, Duan J, et al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature Aug 6 2009;460(7256):753‐757. Schmidt ME, Kent JM, Daly E, Janssens L, Van Osselaer N, Hüsken G, Anghelescu IG, Van Nueten L (2012) A double‐blind, randomized, placebo‐controlled study with JNJ‐37822681, a novel, highly selective, fast dissociating D₂ receptor antagonist in the treatment of acute exacerbation of schizophrenia. Eur Neuropsychopharmacol. Oct;22(10):721‐33. doi: 10.1016/j.euroneuro.2012.02.007. Epub 2012 Mar 31. Stefansson H, Ophoff RA, Steinberg S, et al. (2009) Common variants conferring risk of schizophrenia. Nature Aug 6 2009;460(7256):744‐747. Stein J (2012) Bitopertin decreases negative symptoms in patients with schizophrenia. DocGuide.com. Available at: http://www.docguide.com/bitopertin‐decreases‐negative‐ symptoms‐patients‐schizophrenia?tsid=6 . Accessed on March 20, 2014. Terns RM, Terns MP. (2014) CRISPR‐based technologies: prokaryotic defense weapons repurposed. Trends Genet PMID: 24555991. Wasilewski AI , Rose E (2012) News ‐ Johnson & Johnson Announces Discontinuation Of Phase 3 Development of Bapineuzumab Intravenous (IV) In Mild‐To‐Moderate Alzheimer's Disease. Johnson & Johnson. Available at: http://www.jnj.com/news/all/johnson‐and‐ johnson‐announces‐discontinuation‐of‐phase‐3‐development‐of‐bapineuzumab‐ intravenous‐iv‐in‐mild‐to‐moderate‐alzheimers‐disease . Accessed on March 20, 2014.
Acknowledgements
Conflict of Interest The authors declare no conflicts of interest.
Contributors David Nutt and Anna Need conceived of and wrote this article.
Role of the Funding Source N/A
Where now for schizophrenia research? David J Nutt, Anna C. Need
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Received date: 31 March 2014 Revised date: 17 May 2014 Accepted date: 19 May 2014 Cite this article as: David J Nutt, Anna C. Need, Where now for schizophrenia research?, European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2014.05.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Where now for schizophrenia research? David J Nutt1 Edmond J Safra Prof of Neuropsychopharmacology and Anna C. Need Lecturer in Neurogenetics Division of Brain Sciences Imperial College London 1 Email: [email protected]
Schizophrenia continues to pose a serious challenge to neuroscience and psychiatry as well as to health care systems and to the patients and families who suffer this terrible and disabling illness. Major developments in the past few months in both genetics and drug development oblige us to consider novel drug discovery tactics for future schizophrenia research. Here we review what we consider to be the key issues and some suggested solutions.
Keywords Schizophrenia; Genetics; Serendipity; Glutamate; Clozapine; Antipsychotics Death by a thousand variants: how genetics has fundamentally altered our understanding of schizophrenia In October, Nature Genetics published the results of the latest genome‐wide association study (GWAS) of schizophrenia with close to 60,000 probands and controls (Ripke et al. 2013). No common genetic variant that contributed any meaningful effect was found, nor has anyone expected to find such a variant since the first phase of schizophrenia GWAS were published several years ago (Need et al., 2009; Purcell et al., 2009; Shi et al., 2009; Stefansson et al., 2009) The authors found 22 independent genetic loci that weakly but significantly associated with schizophrenia and used these data to calculate that around 8,000 independent SNPs may collectively be able to explain about half of the genetic contribution to schizophrenia. The remaining hope for GWAS is that some of these thousands of SNPs will implicate genes that converge on a few specific and informative pathways. Convergence on informative pathways is now the residual ambition for schizophrenia sequencing studies as well. An early exome sequencing study ruled out a large contribution from genetic variants of intermediate frequency (Need et al., 2012) , but left open the possibility that a modest number of genes could be important. This hope was just dampened by two much bigger exome sequencing studies published in Nature that failed to find significance support for any individual genes (Fromer et al., 2014; Purcell et al., 2014). Although sequencing studies involving tens of thousands of schizophrenia patients will (hopefully) begin to implicate individual genes, they will each be relevant to only a very small fraction of schizophrenia cases. From an etiological point of view, these studies showed an exciting convergence: all three showed a suggestive enrichment of signals from calcium channel genes and both exome sequencing studies implicate the postsynaptic ARC complex. Unfortunately, while these pathways include tractable drug targets, their ubiquity in the brain means that they are not likely to lead to drugs that are selective for schizophrenia. Indeed, calcium channels have also been implicated by genetic studies of bipolar disorder (Ferreira et al., 2008) and there is some evidence that the calcium channel blocker verapamil may be effective as an add‐on treatment resistant bipolar disorder (Mallinger et. al., 2008). However calcium channels have critical roles in the developing brain and since prevention of schizophrenia may need early pre‐puberty interventions, effective drugs for schizophrenia based on calcium channel antagonism may prove impossible to develop with an acceptable safety margin. There are some other important aspects of these findings. For example some of the most exciting earlier “discoveries” of genes for schizophrenia such as dysbindin and neuregulin (Owen et al., 2005) have not replicated in larger studies, and there is no evidence that variation in genes in the dopamine system (including the infamous COMT) have any role in
schizophrenia. This is a real paradox given that the only drugs that work in the disease are those that block dopamine D2 receptor (DRD2) actions (Kapur and Mamo, 2003). Additionally, where genetic variants have reliably been associated with schizophrenia, either through analysis of copy number variants (CNVs) or very large GWAS, they have indicated a shared genetic etiology across a wide range of brain disorders including schizophrenia, ADHD, bipolar disorder, autism, intellectual disability(Cross‐Disorder Group of the Psychiatric Genomics et al., 2013; Grayton et al., 2012). The end of the age of glutamate? The second recent disappointment in schizophrenia research is the failure of the two phase 3 trials of bitopertin (Grogan, 2014). This is a Roche drug that works to enhance the function of the excitatory neurotransmitter glutamate at the NMDA receptor. A body of preclinical and human postmortem studies have implicated deficient glutamate function, particularly in the prefrontal cortex in aspects of schizophrenia, especially cognition and negative symptoms. Glutamate is far too activating a neurotransmitter to be directly mimicked or potentiated in the brain as anxiety and then seizures are produced. To overcome this obstacle allosteric modulators such as bitopertin and organon 25935 (Christmas et al., 2014) have been developed that more subtly increase glutamate receptor function by increasing the availability of glycine in the synaptic cleft. As glycine is a glutamate potentiator, more glycine means more efficacy of glutamate at the NMDA receptor. Glycine reuptake blockers are safe in humans and a phase 2 trial of bitopertin showed promise as an add‐on in schizophrenia (Stein, 2012). However the failure of the two phase 3 regulatory trials almost certainly means that this drug will not now become a medicine. Moreover, the failure of this major body of work, coupled with the fact that drugs working on other glutamate receptors such as the Lilly metabotropic receptor agonist pomaglumetad methionil (Heimer, 2012) have also failed to show efficacy in phase 3 studies after promising phase 2 results, is likely to have a very deleterious effect on the confidence of other pharmaceutical companies to stay in – let alone enter – this field. Given the highly significant pull out from the psychiatry sector in recent years (Nutt and Goodwin, 2011) this could mark the death‐knell for pharmaceutical investment in new treatments for psychiatric disorders. The bitopertin story shows that developing new drugs based on a theory is very risky. This issue of target specificity in brain drug development is the leading challenge to this field today and the source of great hubris to the neuroscientific field. In the past 30 years there has not been a single drug developed based on a new theory of psychopharmacology; indeed one could argue that in the whole history of psychiatry there have been no conceptual treatment breakthroughs based on neuroscience insights. The drugs we have today are all refinements of those discovered in the 1950s by serendipity. Wherever drug targeting tests a theory it has failed. Another major example other than the glutamate drugs in schizophrenia has been the failure of amyloid‐reducing drugs e.g. bapineuzumab, in Alzheimer's disease (Wasilewski and Rose, 2012). How to remedy the situation? There are many exciting possible directions for developing new schizophrenia treatments but we must be carefully guided by our past successes and failures. There are two unequivocal successes in schizophrenia treatment – that dopamine D2 receptor blocking drugs are effective for some symptoms in a proportion of patients and that clozapine has special efficacy in the more severely ill, treatment resistant patients (Kane et al., 1988). Both facts were discovered by serendipity. The dopamine receptor blocking discovery has been
successfully utilized but may offer more (Schmidt et. al. (2012), clozapine has proved impossible to improve on largely because its special properties are still not understood. Improve current medications Given the apparent genetic heterogeneity of schizophrenia, it is very unlikely that one drug will fix all. Indeed it is remarkable that any drugs can be shown to work on as many people as they do! Dopamine receptor blocking drugs help a significant proportion of patients particularly those with positive symptoms [delusions and hallucinations] and when used with high quality family psychotherapy input can produce very enduring good outcomes (Leff et al., 1982). However they don't work in everyone, possibly because not all patients with schizophrenia have a dopamine related illness. For instance, a small subgroup of schizophrenics may have undiagnosed rare diseases such as limbic encephalitis (Martinez‐ Martinez et. al. 2013). One simple option for improvement in schizophrenia treatment would be to stratify patients using biomarkers that predict drug response. Very encouragingly, a genetic variant was recently identified that very effectively predicts response to lithium in Chinese bipolar patients (Chen et al., 2014). To date, however we have failed to find clinically useful genetic predictors of antipsychotic response in schizophrenia, despite intense research effort. Current evidence from radioimaging studies reveals a subset of schizophrenia patients that have excessive dopamine release to stimulants (Laruelle et al., 1996) or increased dopamine turnover (Fusar‐Poli and Meyer‐Lindenberg, 2013) Cheap and reliable markers of those patients where symptoms are caused by brain dopamine excess could help direct interventions – and those that do not show this should be the prime group in which new treatments should be targeted. Improving dopamine blockers is another tractable approach, since we know what systems we are working with. All current antipsychotics have adverse effects and refining medications to minimise these should be encouraged. This should include development of dopamine blockers with different profiles at other receptor systems e.g. noradrenaline receptors (Litman et al., 1996) and new partial agonists that may improve on the only current one, aripiprazole. Drugs that target the enhanced presynaptic dopamine function seen in some patients, particularly in the prodrome, need to be considered. Here I (DJN) am reminded of a patient seen many years ago whose schizophrenia symptoms improved remarkably for weeks after he had taken a deliberate overdose of his antihypertensive medication L‐methyl‐DOPA [Aldomet]. We presumed that this had effectively depleted his synaptic pool of dopamine for a while, and regret now never writing it up. Would a trial of this be warranted? A moonshot for clozapine? The failure of current science to explain the unique mechanism of action of clozapine is one of the most humbling aspects of the current situation. Hundreds of millions of dollars have been spent by pharmaceutical companies and government research agencies on this problem with no conclusive outcomes. Most companies have now given up the search as they pull out of brain research altogether, and those that are left have much reduced investment. However we know there must be a solution, so how to find it? An integrated network of researchers spanning all aspects of neuroscience and clinical research will be required, just as that which underpinned the successful moonshots. In recent years we have seen specific investments by both Europe and the USA in brain research in an attempt to make significant breakthroughs in conceptual understanding [Human Brain Project
https://www.humanbrainproject.eu/en_GB]. The economic and human rewards offered by cracking the clozapine question could be as great and should be more tractable since the question is more limited. Back to the future? Can we go back to the future and actively seek serendipity? All the current drug classes we use in psychiatry were discovered by astute clinical observation of unexpected effects of drugs used to treat other disorders. In the case of schizophrenia, chlorpromazine was found by testing – in patients – of new sedative drugs. It took more than 5 years for its mode of action (dopamine blockade) to be discovered. Recently another potential treatment for schizophrenia has been similarly found by accident. This is minocycline, an old antibiotic that showed remarkable effects on schizophrenia symptoms in two Japanese patients given it for life threatening infections (Dean et al., 2012). Since then there have been several trials of it as an add‐on to antipsychotic treatments and results have been quite promising (Chaudhry et al., 2012). We now need to work out why minocycline works. It may be that some patients with schizophrenia have latent infections but this seems unlikely. Minocycline has effects a range of effects on microglia, glutamate systems and on neuroinflammation any of which might be significant (Dean et al., 2012). The use of serendipity to discover potential treatments needs to be encouraged. Although well‐established processes for declaring adverse effects of drugs exist, the same is not true for the reporting of beneficial effects. Traditionally this would have occurred as case reports but many journals have now eliminated these as they reduce their impact factor. So new avenues for reporting such cases need to be developed. Case reports may be difficult to publish in journals, but a publically accessible web page could be used to rapidly report and disseminate suspected antipsychotic, antidepressant or anxiolytic effects of existing drugs, just as they are for one‐off associations of genetic variants with disease (e.g., Decipher http://decipher.sanger.ac.uk/). Such potential new therapeutic insights are unlikely to be taken up by the pharmaceutical companies so other approaches are required. Such studies could be modeled on the open label ones such as those of Delay and Deniker (1952) and Kuhn (1958) that identified the special properties of chlorpromazine and imipramine i.e. in small well defined patient cohorts. National or international networks to allow this should be set up and funded. Also such expert centres would also allow the training of the next generation of clinical researchers. Serendipity also can exist at the preclinical level. Some drugs for other indications might have some impact in brain disorders, particularly intracellular targets such as enzymes and inflammatory modulators. However modern pharmaceutical research processes are very focused on single diseases, and this usually precludes these compounds being tested in models of brain function. Indeed many pharmaceutical companies now have no interest or in‐house expertise in brain pharmacology at all. If these drugs make it to the clinic then they can be tested by others but if they do not then they usually become extinct, a lamentable loss of scientific knowledge and opportunity (Nutt et al., 2014). At the very least these compounds should be put into the public domain as soon as possible after they cease to be of commercial value. Can genetics rise from the ashes? It is clear that the genetics of schizophrenia is not going to be simple, and most findings will not be rapidly clinically applicable, if at all. However there may be some exceptions. There
are currently several groups and consortia that are whole‐genome sequencing very large numbers of schizophrenia patients, and we can expect one, and hope for a second, important outcome. The first is that some patients will have causal mutations in genes that are already drug targets, and these patients may respond to already approved treatments that would never have been trialed for schizophrenia patients otherwise. The second outcome, that many are pinning their hopes on, is that a ‘new DRD2’ will be discovered. This is not of course a literal hope for a new dopamine receptor, rather that associated genes will begin to converge on an unexpected molecular pathway, which can be targeted either with new or existing medications. Improving back translation The relevance of mutant mouse models may seem to be diminished if any schizophrenia‐ associated genetic variant either has only a miniscule additive effect on risk, or is seen only in one or a few patients. Certainly the hope that a mutant mouse could faithfully reproduce human psychiatric disorders has always been an exercise more of faith than certainty; mouse brains are significantly different in size and cortical structure, and schizophrenia diagnosis is based on reports of symptoms that would be impossible to measure in mice even if they could be recreated. Mouse genetic models may nevertheless play a part in the identification of schizophrenia genes and their subsequent guidance for treatments. With sample sizes in the tens or hundreds of thousands, it is very likely that some genes will be statistically demonstrated to have very highly penetrant schizophrenia associated genetic variants. However, there will be many more genes that are not mutated in enough patients to reach this threshold. With novel technologies such as CRISPR (Terns and Terns, 2014), we can introduce known schizophrenia‐associated mutations in mice and look at their effects on other gene products. Genes or gene products that are explicitly affected by known schizophrenia‐associated mutations may have damaging mutations in other patients, and these can be prioritized for targeted sequencing studies in larger cohorts, expanding the list of definitively associated genes. Similarly, such mouse models can be used to reveal novel molecular pathways that schizophrenia mutations are converging on, and potentially identify our hypothetical ‘new DRD2’ (Kapur and Mamo, 2003). Mice (and rats) can also help us without being mutated. The dopamine blocking actions of chlorpromazine were discovered using simple pharmacological challenge tests in rodents. Dopamine was enhanced by giving the precursor L‐dopa and a releaser amphetamine, and the subsequent behavioural activation was blocked by chlorpromazine. All other antipsychotics were validated with the same assays. Such a simple screen allows us to test many thousands of new compounds for the ability to decrease dopamine hyperactivity. Some of these might work through novel mechanisms i.e. other than by direct receptor blockade, and could offer new approaches to treatment. Encourage symptom targeting If we can’t treat the disease of schizophrenia then at least we can help reduce symptoms. This is what antipsychotics do; they block dopamine D2 receptors and this somehow reduces positive symptoms, possibly by altering the perceived salience of sensory inputs (Kapur, 2003). However, there are many other symptoms in schizophrenia with cognitive and motivational problems being prominent, and indeed the major cause of disability. It is becoming accepted by regulatory bodies that approaching these with medicines is an acceptable way to progress, though none has yet been licensed. The challenges and
methodologies for this approach to cognition in schizophrenia has recently been the subject of a major consensus meeting (Nutt et al., 2013). Similar approaches to negative symptoms are being developed e.g. the use of amphetamines to enhance motivation and reduce negative symptoms in patients treated with antipsychotics (to prevent the positive symptoms worsening) (Lasser et al., 2013). Look into the brain Another approach that has been much touted is that of measuring brain processes, particularly with imaging, to identify schizophrenia‐associated neural features, and then trying to remedy them with new treatments. Such neural features are known as ‘endophenotypes’ and are also present in unaffected family members, who can be more easily studied without the confounding effects of antipsychotic treatments. The traditional theory of endophenotypes is based on a threshold model, in which multiple genetic variants contribute to schizophrenia in an additive manner (Gottesman and Gould, 2003). Close relatives are assumed to have many of the disease‐associated alleles, but not enough to push them over the edge into disease. However, in recent years it has been discovered that some schizophrenia patients have single genetic variants that have a very strong effect on disease risk, and thus do not adhere to the threshold model. Despite their strong effects, in some cases these variants are inherited from parents or carried by siblings that do not have schizophrenia. These unaffected carriers can have abnormalities similar to their patient relatives that could be explored for drug response (Spence et al., 2000). Of course the fact that they do not have schizophrenia means that in some (as yet unknown) ways their brains are different and the effect of this may interfere with the results of the drug testing. Humans, too, can be useful without being mutated. As for mice, aspects of schizophrenia can be modeled in normal healthy volunteers by giving them drugs that profoundly alter their brain such as psychedelics, cannabis or ketamine (Carhart‐Harris et al., 2013). The challenge here is to find medicines that block the effects of these drug challenges without directly interfering with the challenges pharmacology. So atypical antipsychotics will block the effects of psychedelics just because they block the 5HT2A receptors to which psychedelics bind. Interesting new developments here include the use of MRI measures of brain connectivity that are disrupted by drugs such as psychedelics and ketamine in a similar fashion to that seen in schizophrenia (Carhart‐Harris et al., 2012). New agents e.g. a tyrosine‐kinase inhibitor, are currently being tested in this model of schizophrenia (MRC/AstraZeneca: Mechanisms of Disease Call assets, http://www.mrc.ac.uk/Fundingopportunities/Calls/MoD/compounds/index.htm) and if these work in the lab – and then are validated in the clinic – this may prove a useful way forward. Conclusions Schizophrenia remains a common and very damaging brain disease that presents a serious challenge to neuroscience and clinical therapeutics. The hoped‐for advances that the genetic revolution offered have not yet materialized, and we remain, as ever, looking for answers that seem to lie just round the next technological corner. Moreover, treatment advances based on neuropathology and animal models of glutamate dysfunction have also failed. We need now to digest the implications of these disheartening findings and develop new research strategies that will give succor to research funders as well as the pharmaceutical industry and give hope to patients and their families.
Some of these will involve more pragmatic and “mundane” research and less‐theory based approaches, and the funding of these will require some changes in the way research is viewed by funding agencies. Also structural funding sources could be used for setting up research centres instead of for example new roads. Others require the international pooling of insights and data on the drugs that do work, particularly clozapine, to develop newer safer alternatives. For this to work there needs to be widespread buy‐in from funders, regulators and scientists. Dedicated funds to support serendipity might be made available e.g. to collect data of positive but unexpected effects on schizophrenia and related syndromes induced by other medicines (see the recent report that warfarin might reduce symptoms http://www.medscape.com/viewarticle/825210). These could be run alongside national databases that collect information on the adverse effects of medicines. References Carhart‐Harris R, Brugger S, Nutt D, Stone J (2013) Psychiatry's next top model: cause for a re‐think on drug models of psychosis and other psychiatric disorders. J Psychopharmacol. 2013 Jun 19. [Epub ahead of print] PMID: 23904408. Carhart‐Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Hobden P, Evans J, Sharp DJ, Feilding A, Wise RG, Nutt DJ (2012) Imaging the brain mechanisms of disturbed ego‐ boundaries following psilocybin: a model for prodromal psychosis? Schizophrenia Bulletin 39(6):1343‐51. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn, G, Deakin B (2012) Minocycline benefits negative symptoms in early schizophrenia: a randomised double‐blind placebo‐controlled clinical trial in patients on standard treatment J Psychopharmacol September 2012 vol. 26 no. 9 1185‐1193 doi: 10.1177/0269881112444941. Chen CH, Lee CS, Lee MT, et al. (2014) Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med Jan 9 2014;370(2):119‐128. Christmas D, Alison Diaper A, Wilson S, Rich A, Phillips S, Udo de Haes J, Sjogren M, Nutt DJ (2014). A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers. Human Psychopharmacology Jan 14. doi: 10.1002/hup.2384. [Epub ahead of print]. Cross‐Disorder Group of the Psychiatric Genomics, et al. (2008) Collaborative genome‐wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40, 1056‐1058. Dean OM, Data‐Franco J, Giorlando F, Berk M (2012) Minocycline CNS Drugs: 5:391‐401. Delay J, Deniker P. (1952) Le traitement des psychoses par une me´thode neurolytique de´rive´e de l’hibernothe´rapie. (le 4560 R.P. utilise´ seul en cure prolonge´e et continue.) CR Congre`s Me´d Alie´n Neurol (France) 1952;50:497–502. Ferreira, MA, O'Donovan, MC, Meng, YA, et. al. (2008) Collaborative genome‐wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40, 1056‐1058.
Fromer M, Pocklington AJ, Kavanagh DH, et al. (2014) De novo mutations in schizophrenia implicate synaptic networks. Nature Feb 13 2014;506(7487):179‐184. Fusar‐Poli P, Meyer‐Lindenberg A (2013) Striatal presynaptic dopamine in schizophrenia, Part II: meta‐analysis of [18F/11C]‐DOPA PET studies ‐ Schizophrenia bulletin, 2013. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry Apr 2003;160(4):636‐645. Grayton HM, Fernandes C, Rujescu D, and Collier DA (2012) Copy number variations in neurodevelopmental disorders. Prog. Neurobiol. 99: 81‐91 Grogan K (2014) Setback for Roche schizophrenia drug bitopertin. PharmaTimes online. Available at: http://www.pharmatimes.com/article/14‐01‐ 21/Setback_for_Roche_schizophrenia_drug_bitopertin.aspx . Accessed on March 20, 2014. Heimer H (2012) News Brief—Dead End for Lilly mGluR Schizophrenia Drug. Schizophrenia Research Forum. Available at: http://www.schizophreniaforum.org/new/detail.asp?id=1797 . Accessed on March 20, 2014. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the Treatment‐Resistant Schizophrenic: A Double‐blind Comparison With Chlorpromazine Arch Gen Psychiatry 45(9):789‐796. doi:10.1001/archpsyc.1988.01800330013001. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry 160:13‐23. doi:10.1176/appi.ajp.160.1.13. Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progress in Neuro‐Psychopharmacology and Biological Psychiatry Volume 27, Issue 7, October 2003, Pages 1081–1090. KUHN R. (1958) The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958 Nov;115(5):459‐64. PubMed PMID: 13583250. Laruelle M, Abi‐Dhargham A, Van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbii SS, Baldwin RM, Seibyli JP, Krystal JH, Charney Down's Syndrome , Innis RB. (1996) Single photon emission computerized tomography imaging of amphetamine‐induced dopamine release in drug‐free schizophrenic subjects. Proc. Natl.Acad. Sci. USA Vol. 93, pp. 9235‐9240, August 1996 Neurobiology. Lasser RA, Dirks B, Nasrallah H, Kirsch C, Gao J, Michael L Pucci ML, Knesevich MA, Lindenmayer J‐P (2013) Adjunctive Lisdexamfetamine Dimesylate Therapy in Adult Outpatients With Predominant Negative Symptoms of Schizophrenia: Open‐Label and Randomized‐Withdrawal Phases. Neuropsychopharmacology (2013) 38, 2140–2149; doi:10.1038/npp.2013.111; published online 12 June 2013. Leff J, Kuipers L, R Berkowitz R, Eberlein‐Vries R, Sturgeon D. [1982] A controlled trial of social intervention in the families of schizophrenic patients. The British Journal of Psychiatry (1982) 141: 121‐134 doi: 10.1192/bjp.141.2.121.
Litman RE, Su TP, Potter WZ, Hong WW and Pickar D (1996) Idazoxan and response to typical neuroleptics in treatment‐resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Brit J Psychiatry 1996, 168:571‐579. DOI: 10.1192/bjp.168.5.571. Mallinger AG, Thase ME, Haskett R, Buttenfield J, Luckenbaugh DA, Frank E, Kupfer DJ, Manji HK. (2008) Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.Bipolar Disord. Dec;10(8):856‐66. doi: 10.1111/j.1399‐5618.2008.00636.x. Martinez‐Martinez P1, Molenaar PC, Losen M, Stevens J, Baets MH, Szoke A, Honnorat J, Tamouza R, Leboyer M, Os JV, Rutten BP. (2013) Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders. Front Genet. Sep 20;4:181. eCollection 2013. Need AC, Ge D, Weale ME, et al. (2009) A genome‐wide investigation of SNPs and CNVs in schizophrenia. PLoS genetics Feb 2009;5(2):e1000373. Need AC, McEvoy JP, Gennarelli M, et al. (2012) Exome sequencing followed by large‐scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet Aug 10 2012;91(2):303‐312. Nutt D, Gispen‐de Wied CC, Arango C, Keefe RS, Penadés R, Murphy DG, Robbins TW, Sahakian BJ (2013) Cognition in schizophrenia: Summary Nice Consultation Meeting 2012. Eur Neuropsychopharmacol. May 15. pii: S0924‐977X(13)00100‐4. doi: 10.1016/j.euroneuro.2013.03.005. Nutt D, Goodwin G. (2011) ECNP Summit on the future of CNS drug research in Europe 2011: report prepared for ECNP by David Nutt and Guy Goodwin. Eur Neuropsychopharmacol. 21(7):495‐9. PMID: 21684455. Nutt DJ, Hayes A, Kilpatrick G (2014) The extinction of drugs for clinical research: can the ECNP Medicines Chest save them? European Neuropsychopharmacology ‐ in press. Spence SA, Grasby PM, Liddle PF (2000) Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk Focal dysfunction and distributed disconnectivity reappraised The British Journal of Psychiatry (2000) 176: 52‐60 doi: 10.1192/bjp.176.1.5. Owen MJ, Craddock N, O'Donovan MC. (2005) Schizophrenia: genes at last? Trends Genet Sep 2005;21(9):518‐525. Purcell SM, Moran JL, Fromer M, et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature Feb 13 2014;506(7487):185‐190. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature Aug 6 2009;460(7256):748‐752. Ripke S, O'Dushlaine C, Chambert K, et al. (2013) Genome‐wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet Aug 25 2013.
Shi J, Levinson DF, Duan J, et al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature Aug 6 2009;460(7256):753‐757. Schmidt ME, Kent JM, Daly E, Janssens L, Van Osselaer N, Hüsken G, Anghelescu IG, Van Nueten L (2012) A double‐blind, randomized, placebo‐controlled study with JNJ‐37822681, a novel, highly selective, fast dissociating D₂ receptor antagonist in the treatment of acute exacerbation of schizophrenia. Eur Neuropsychopharmacol. Oct;22(10):721‐33. doi: 10.1016/j.euroneuro.2012.02.007. Epub 2012 Mar 31. Stefansson H, Ophoff RA, Steinberg S, et al. (2009) Common variants conferring risk of schizophrenia. Nature Aug 6 2009;460(7256):744‐747. Stein J (2012) Bitopertin decreases negative symptoms in patients with schizophrenia. DocGuide.com. Available at: http://www.docguide.com/bitopertin‐decreases‐negative‐ symptoms‐patients‐schizophrenia?tsid=6 . Accessed on March 20, 2014. Terns RM, Terns MP. (2014) CRISPR‐based technologies: prokaryotic defense weapons repurposed. Trends Genet PMID: 24555991. Wasilewski AI , Rose E (2012) News ‐ Johnson & Johnson Announces Discontinuation Of Phase 3 Development of Bapineuzumab Intravenous (IV) In Mild‐To‐Moderate Alzheimer's Disease. Johnson & Johnson. Available at: http://www.jnj.com/news/all/johnson‐and‐ johnson‐announces‐discontinuation‐of‐phase‐3‐development‐of‐bapineuzumab‐ intravenous‐iv‐in‐mild‐to‐moderate‐alzheimers‐disease . Accessed on March 20, 2014.
Acknowledgements
Conflict of Interest The authors declare no conflicts of interest.
Contributors David Nutt and Anna Need conceived of and wrote this article.
Role of the Funding Source N/A
