By Charlie Taylor, Regulatory Writer and Drug Development Consultant, MMS Holdings
Neuroscience continues to advance rapidly, with tens of thousands of new peer-reviewed articles each year. Several findings stood out to me in 2014 as being relevant for neurology and psychiatry drug discovery and development. This summary scratches the surface…
Clinical Neuroscience Studies:
- Cognitive deficits in schizophrenia are a huge unmet challenge because existing antipsychotic drugs do little to help impaired memory, planning for the future and “emotional IQ.” Santarelli and colleagues, in a trial with schizophrenia patients (Umbricht, Keefe et al. 2014), found that RG3487, an alpha-7 specific nicotinic partial agonist, improved thinking deficits (Negative Symptom subscore) in a subset of schizophrenia patients. Treatment effects were large (about 25% of the total negative symptoms score) and dose-related. These results are very encouraging for future treatment of schizophrenia negative symptoms and also may explain why more than 60% of patients with schizophrenia smoke.
- Alzheimer’s disease is a huge healthcare challenge that, despite intense drug discovery efforts for over 30 years, remains mostly untreatable. Behavioral agitation, mood swings and aggression in Alzheimer’s are a particular burden to health care providers. Physicians have been criticized for overusing major tranquilizers (antipsychotic drugs) to reduce agitation. Although effective, such treatments sedate patients and compromise memory and thinking. In contrast, a new formulation of dextromethorphan plus quinidine (Nuedexta®) reduced agitation in Alzheimer’s patients without sedation. Dextromethorphan is the active ingredient in most over-the-counter cough suppressants and quinidine is an older cardiovascular drug now used in small amounts to greatly reduce dextromethorphan metabolism. In apparent reaction to the clinical trial news, Avanir stock increased in value 3-fold and Otsuka Pharmaceuticals announced plans to acquire Avanir for about $3.5 billion.
- New drugs intended to prevent the progression of early Alzheimer’s have been the focus of dozens of drug discovery efforts over the past 20 years. A review of anti-amyloid treatments for Alzheimer’s disease (Karran and Hardy 2014) critically discussed results from 6 different drugs that completed randomized placebo-controlled clinical trials. Overall results were disappointing, with no clear indication that any treatment slowed the advancement of disease. This leaves the field in doubt as to whether any future treatment to reduce amyloid aggregation in the brain will ever successfully treat Alzheimer’s disease.
Laboratory Basic Neuroscience Studies:
- The 2014 BRAIN Initiative promotes collaboration across U.S. agencies, academic laboratories and the private sector to increase understanding of the human brain using techniques such as large electron microscope serial section reconstructions and large-scale computer simulations that are costly and labor intensive. This initiative supports large studies such as the Human Connectome Project and recording methods that monitor hundreds of brain neurons simultaneously. Older techniques such as single-neuron electrical recordings, although very useful, have been likened to analyzing a football game by watching the responses of a single fan in the stands. Additional steps forward in understanding brain function will require progressively bigger advances in technology.
- A review of genes that contribute to psychiatric disease (Gratten, Wray et al. 2014) showed that psychiatric and neurological disorders usually result from many different genes that each contribute a very small risk for disease. For example, over 125 known genes contribute to schizophrenia, 20 contribute to Alzheimer’s disease and 8 to bipolar disorder. No genetic risk factors are known for ADHD, anorexia, major depressive disorder or obsessive-compulsive disorder. In schizophrenia, no single gene contributes more than 4% of the overall risk for disease. In contrast, overall genetic heritability of schizophrenia, major depression and autism are each between 40% and 80% (judged by family tree analysis). Therefore, although heritability of psychiatric disease is relatively high, identification of single genes seems unlikely to uncover future treatments that are useful for the entire disease population. The remaining non-genetic risk of disease is presumed to be caused by environmental factors and de novo mutations and gene duplications that are not inherited. In summary, the hope that sequencing the human genome would lead directly to useful medical treatments for common psychiatric diseases seems unrealistic.
- John O’Keefe, May-Brit Moser and Edvard Moser shared a 2014 Nobel Prize for their work to describe how neurons in the hippocampus and entorhinal cortex determine position and enable spatial navigation. They discovered “place cells” and “grid cells” that react to visual cues when an animal occupies one spot or moves through 3-D space. This system has been called the brain’s GPS and it also is used to organize memory of sequences of events. Their approach is one of the first to yield new understandings on the mechanisms of abstract thinking that is not directly linked to sensory or motor function.
- New results helped understand how the brain manipulates the “good or bad” associated with memories. Tonegawa and colleagues at MIT (Redondo, Kim et al. 2014) manipulated a set of neurons in mouse hippocampus and changed the “polarity” of memories from bad (a specific place where mice received foot shocks) to good (a place where mice were exposed to sexually receptive female mice) and vice versa. This was done by selectively activating neurons in the dorsal dentate gyrus of the hippocampus with light pulses that activated neurons while mice were exposed to either positive or negative reinforcement. These results give hope that specific future treatments for post-traumatic stress syndrome and other negative memories might be discovered in humans.
- During 2014, evidence continues to emerge that sleep disturbances may cause memory problems seen with Alzheimer’s, aging, depression and schizophrenia…And sleep disturbance may contribute directly to the progression of Alzheimer’s disease. These findings suggest that drug treatments or lifestyle changes that specifically improve sleep quality (for example, increasing phase 4 or deep sleep and reducing sleep disruptions) may improve cognitive deficits and also prevent Alzheimer’s disease progression.
o Artificially increasing a natural protein in the hippocampus of mice (phosphorylated eukaryotic translation initiation factor 43 binding protein or 4EBP2) helps retain spatial memories that otherwise degrade with sleep deprivation. This indicates that the mammalian target of rapamycin (mTOR) biochemical pathway is compromised with sleep loss, causing memory deficits (Choi, Davis et al. 2014). The mTOR pathway is activated by many different stimuli that each cause new transcription of DNA and synthesis of new proteins inside of neurons.
o Sleep disturbance also may contribute directly to disease progression in Alzheimer’s disease. Maiken Nedergaard and colleagues at University of Rochester (Xie, Kang et al. 2013) found that fluid flow within the brain increases up to 10-fold with slow-wave sleep compared to waking in rats. They propose that metabolic byproducts and amyloid protein accumulate in brain with lost sleep, and this contributes directly to Alzheimer’s disease. In a follow-up paper (Kress, Iliff et al. 2014) they found that brain tissue clearance of amyloid protein is impaired 40% in aged mice compared to young mice. They also showed that the glial ion channel aquaporin-1 is lost in astrocytes of aged mice. The same group (Iliff, Chen et al. 2014) found that head trauma causes glial scars that substantially reduce brain fluid flow. It has long been known that head trauma is a major risk factor for subsequent Alzheimer’s, and this is the first study to directly suggest why.
- (El-Boustani and Sur 2014) used electrophysiology of single brain neurons and calcium imaging of a large network of neurons together with genetically-engineered light stimulation (optogenetics) to study inhibitory GABA interneurons. The GABA neurons either caused subtractive or divisive inhibition at their target cells, depending on the timing of inhibition with relation to excitation in the neurons they innervate. This finding will provide a better overall understanding and better modelling of neuronal networks in neocortex.
Overall, these advances in neuroscience underscore a couple of conclusions. Firstly, many approaches to treating Alzheimer’s and other serious mental disorders, although based on solid logic and promising results in animal models, have failed miserably in clinical trials. This, unfortunately, is a common fact of life for drug discovery. Secondly, promising findings often emerge from approaches that at first seem trivial (such as improving sleep quality in schizophrenia or Alzheimer’s disease). Undoubtedly, as progress continues toward understanding the brain and mind, future therapies for common disabling diseases such as depression, schizophrenia and Alzheimer’s will emerge that are much different from those in use today.
1. Choi JH, Davis EJ, Havekes R and Abel T (2014). Restoration of phosphorylated eukaryotic translation initiation factor 4E binding protein 2 (4EBP2) in the hippocampus rescues memory impairment due to sleep deprivation Soc. Neurosci. Abstracts 291.07.
2. El-Boustani S and Sur M (2014). Response-dependent dynamics of cell-specific inhibition in cortical networks in vivo. Nat Commun 5: 5689.
3. Gratten J, Wray NR, Keller MC and Visscher PM (2014). Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17(6): 782-790.
4. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R and Nedergaard M (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34(49): 16180-16193.
5. Karran E and Hardy J (2014). A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol 76(2): 185-205.
6. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R and Nedergaard M (2014). Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76(6): 845-861.
7. Redondo RL, Kim J, Arons AL, Ramirez S, Liu X and Tonegawa S (2014). Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513(7518): 426-430.
8. Umbricht D, Keefe RS, Murray S, Lowe DA, Porter R, Garibaldi G and Santarelli L (2014). A randomized, placebo-controlled study investigating the nicotinic alpha7 agonist, RG3487, for cognitive deficits in schizophrenia. Neuropsychopharmacology 39(7): 1568-1577.
9. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R and Nedergaard M (2013). Sleep drives metabolite clearance from the adult brain. Science 342(6156): 373-377.