Searching for new schizophrenia treatments
Dr. Alfredo Ramos-Miguel is a 2013 MSFHR/BC Schizophrenia Society Foundation Research Trainee Award recipient. In this blog post, he describes the search for new drug compounds to treat the cognitive symptoms of schizophrenia.
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Schizophrenia is a complex and disabling mental disorder with a lifetime prevalence of about 0.7-1.0% worldwide, although some epidemiologists have reported higher rates among the Canadian population [1, 2]. The broad variety of symptoms that characterize schizophrenia fall either into positive, negative or cognitive symptoms.
Positive symptoms are those that typically respond to antipsychotic medication, including delusions, disorganized and abrupt speech, hallucinations, and movement disorders. Negative symptoms, which barely respond to currently available antipsychotic drugs, include inability to experience pleasure (anhedonia) or empathy for others (blunted affect), complete absence of meaningful short-term projects or motivations (avolition) and vanished expectations for social relationships (asociality).
The third “basket” of schizophrenia-related symptoms is directly connected to impaired cognition. Cognitive symptoms dramatically interfere with working memory, executive functioning and awareness skills, frustrating the capacity of people with schizophrenia to develop their learned abilities normally. Similar to negative symptoms, no medication has proven effective for the treatment of cognitive symptoms.
New treatment strategies
A major focus in current schizophrenia research is the development of new drugs that target negative and/or cognitive symptoms. Our recent findings using postmortem brains of deceased individuals with a documented history of schizophrenia have suggested that impaired cognition may result from altered presynaptic function in cortical and subcortical regions of the brain [3, 4], which opens a new strategy for drug design.
What does this mean? To answer this question, we must first understand how neurons and synapses work. In terms of their communication abilities, neurons are by far the most sophisticated cells in the human body. Synapses are the “hot spots” where the communication between two neurons occurs. An average neuron establishes about one thousand synapses with its neighbours, which in turn are connected to a similar number of neurons, building extremely complex pathways and networks across the brain. Communication flow along these intricate networks results in the extraordinary combination of memories, thoughts and feelings we experience in our lives.
In the microscopic world of neurons, the information submitted through the synapses is unidirectional, so the presynaptic terminal of one neuron sends a “message” to its postsynaptic partner (see Figure 1). Messages come in the form of chemical substances called neurotransmitters, more than 60 of which have been discovered in the human brain. Neurotransmitters are initially confined into vesicles inside the presynaptic terminal. When this terminal is stimulated, vesicles fuse into the presynaptic membrane and release the enclosed neurotransmitters into the synapse, crossing the gap between the presynaptic and postsynaptic terminals, and finally activating the postsynaptic neuron through receptors specifically designed to recognize those chemical substances.
Every step of this process is highly regulated by hundreds of specialized proteins, each one with a programmed function. Particularly, three presynaptic proteins are essential for vesicle approach and fusion, two of them –syntaxin and SNAP-25– embedded in the terminal membrane, and the third –VAMP– located in the vesicle membrane. When the terminal is excited, calcium ions are able to enter, which dramatically increases the affinity of these three proteins in order to form a tight, stable structure known as a SNARE complex.
Towards a treatment breakthrough
With this background, our research has focused on the potential role of SNARE proteins and SNARE complexes in schizophrenia. We know that SNARE proteins are crucial in brain development and that subtle genetic alterations have been closely associated with a wide range of mental illnesses, including schizophrenia, ADHD, various forms of intellectual disabilities, dementia, and epilepsy.
Increased interactions between SNARE proteins are among the most consistent findings across postmortem brain studies of individuals with schizophrenia [3, 5]. Moreover, a recent report has highlighted that the number of brain SNARE complexes is directly related to cognitive decline in older adults . We therefore believe that a greater efficiency of SNARE proteins in forming active complexes could eventually result in unbalanced neurotransmission and may contribute to impaired cognition in schizophrenia.
We have hypothesized that molecules able to disrupt the SNARE complex can potentially relieve the cognitive symptoms associated with schizophrenia. Our team has already started the search for such compounds in collaboration with the Centre for Drug Research and Development, and has obtained support from MSFHR and the BC Schizophrenia Society Foundation.
The ongoing project has already screened various libraries containing up to 26,000 compounds, and aims to screen more than one million by completion. This initial screening has identified at least four candidate molecules with promising effects in vitro. Future experiments in animal models –and hopefully in further human trials– may prove the efficacy of these drugs on inhibiting SNARE complex formation and, eventually, treating schizophrenia.
Partial results from this study were presented in Barcelona October 5-9 at the 26th European College of Neuropsychopharmacology (ECNP) Congress, a prestigious scientific meeting of more than 5,000 psychiatrists, pharmacologists, and other basic and clinical researchers.
Jablensky A (1997) The 100-year epidemiology of schizophrenia. Schizophr Res 28: 111-125.
Dealberto MJ (2013) Are the rates of schizophrenia unusually high in Canada? A comparison of Canadian and international data. Psychiatry Res (in press) doi: pii: S0165-1781(13)00006-1. 10.1016/j.psychres.2013.01.002.
Barakauskas VE, Beasley CL, Barr AM, Ypsilanti AR, Li HY, Thornton AE, Wong H, Rosokilja G, Mann JJ, Mancevski B, Jakovski Z, Davceva N, Ilievski B, Dwork AJ, Falkai P, Honer WG (2010) A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia. Neuropsychopharmacology 35: 1226-1238.
Gil-Pisa I, Munarriz-Cuezva E, Ramos-Miguel A, Urigüen L, Meana JJ, García-Sevilla JA (2012) Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. Int J Neuropsychopharmacol 2012 Jun;15(5):573-88.
Honer WG, Falkai P, Bayer TA, Xie J, Hu L, Li HY, Arango V, Mann JJ, Dwork AJ, Trimble WS (2002) Abnormalities of SNARE mechanism proteins in anterior frontal cortex in severe mental illness. Cereb Cortex 12: 349-356.
Honer WG, Barr AM, Sawada K, Thornton AE, Morris MC, Leurgans SE, Schneider JA, Bennett DA (2012) Cognitive reserve, presynaptic proteins and dementia in the elderly. Transl Psychiatry 2: e114.