Dr Samuel Clark – Kappa Opioid Receptors: A New Treatment Target for Schizophrenia
Schizophrenia is a serious psychiatric disorder that affects around 1% of the global population, producing debilitating symptoms that significantly impact upon the quality of life of sufferers. Even with treatment, prognosis is often poor with a high risk of relapse. Dr Samuel Clark of Terran Biosciences Inc and colleagues at Stony Brook University, New York, are investigating the potential of blocking one type of opioid receptor in the brain – the kappa receptor – to reduce the symptoms of the disease.
Schizophrenia and the Need for Novel Interventions
Schizophrenia is a complex and often lifetime disorder, associated with a wide range of symptoms across different domains. The positive symptoms include hallucinations and delusions, often associated with psychosis, whereas the negative symptoms include social withdrawal and reduced expression of emotion. Another cluster of symptoms has been described as cognitive, referring to the deficits to attention and memory.
Despite decades of investigation into the causes and underlying neurobiological features of schizophrenia within the brain, the treatments that are currently available are far from perfect – or even effective for all patients. Existing treatments often only ameliorate the positive symptoms leaving other symptoms untreated. Furthermore, existing treatments frequently come with unpleasant side-effects that, understandably, diminish the motivation of patients to adhere to their prescribed medication regime.
Opioid Receptors in the Brain
Dr Samuel Clark and colleagues at Terran Biosciences Inc and Stony Brook University, New York, are investigating the specific role of the kappa opioid receptor in schizophrenia. Kappa is one of the three different types of opioid receptor in the brain – the others are known as mu and delta. Common painkilling opioids, such as morphine, attach to the mu opioid receptors. However, other drugs can activate the other receptors, or even all of them, at the same time.
Opioid drugs are commonly known for their medical application in providing analgesia but also for recreational abuse and addiction. In simple terms, opioids work by attaching to specific proteins, the opioid receptors. When this happens, the drugs and the receptors fit together like a key in a lock. When opioids attach to opioid receptors, they cause the release of chemical messages creating specific patterns of activation in the brain, primarily associated with the relief of physical and psychological pain.
There are also drugs that block the opioid receptors, stopping them from becoming active and thus exerting their effects. Returning to the key analogy of activation by a drug on a receptor, a receptor blocker is the equivalent of a blank key being put into that lock. It fits but doesn’t work, and critically, stops another key from being used at the same time.
‘Opioid antagonists are potentially very effective treatments for schizophrenia.’
The Kappa Opioid Receptor
In an attempt to develop drugs with the same effects as existing opioids but without the potential for abuse and addiction, researchers turned their investigations to the kappa opioid receptor. As early as in the 1970s it had been discovered that activation of the kappa receptor was as effective as that of the mu receptor in terms of providing pain relief. Thus, several drugs were developed to specifically and selectively activate only the kappa receptor but these were found to have very different effects to the existing opioid drugs. Healthy participants in clinical trials reported severe hallucinations and delusional thinking – very similar to psychosis experienced by people with schizophrenia. On this basis, clinical trials exploring the analgesic properties of drugs activating the kappa receptor were terminated.
Shortly afterwards, other researchers started investigating whether blocking all three types of opioid receptor would have the opposite effect in patients who already had schizophrenia. Lars M Gunne and colleagues conducted a small pilot study exploring the effects of intravenous naloxone, a synthetic drug that blocks the kappa, mu, and delta opioid receptors. Dr Clark describes these findings as ‘miraculous…the patients with schizophrenia had immediate loss of hallucinations on top of what was achieved with standard antipsychotic therapy.’
Further studies ensued with the aim of replicating these promising initial findings. Although the majority reported that patients experienced significant improvement in their schizophrenic symptoms, a number of studies reported a lack of efficacy. This meant that research exploring the potential of kappa opioid receptor blockers as a novel treatment target in schizophrenia was pushed aside – until very recently.
Dr Clark and colleagues recently conducted a review of all of the clinical trials that have examined the impact of kappa antagonists in schizophrenia. In consideration of this, Dr Clark explains, ‘many of the studies that failed to find an effect used older less reliable diagnostic criteria and nearly all studies were underpowered,’ before concluding that ‘opioid antagonists are potentially very effective treatments for schizophrenia.’
Having now also published the first comprehensive review of the literature in this field, Dr Clark and his colleagues can point to a wealth of research that supports the idea that blocking the kappa opioid receptor should act as a highly effective treatment for the range of symptoms associated with schizophrenia. These key papers have brought this line of investigation back to the fore, many years after the potential significance of the kappa opioid receptor in schizophrenia had been identified.
Determining the Underlying Mechanisms
Original thought was that the neurotransmitter dopamine, released as a chemical messenger to allow certain brain cells to communicate, was of particular importance in schizophrenia. Dopamine plays a key role in a host of different activities and experiences, including sleep, mood, learning, and the feeling of pleasure. A stable amount of dopamine is essential to the healthy functioning of our brains, and disruptions to its supply have been implicated in a variety of conditions, in addition to schizophrenia.
As such, treatments for schizophrenia have typically targeted dopamine receptors and this represents the dominant approach in current pharmacological therapies. However, these approaches do not satisfactorily alleviate all symptoms. On the basis of their extensive research, Dr Clark and his team propose that kappa opioid receptors are the underlying culprit underpinning the unstable dopamine levels traditionally associated with schizophrenia, and that these receptors should be targeted together with dopamine receptors themselves.
Importantly, kappa opioid receptors play a role in regulating the amount of dopamine that is released in our brains. If the kappa opioid receptors are not functioning properly – as Dr Clark and his team hypothesise is the case in people with schizophrenia – then they are not performing their anticipated role in maintaining the production of a stable amount of dopamine.
‘Amazingly, these drugs provide a large benefit above and beyond whichever antipsychotic therapy the patients are currently taking. Perhaps most importantly, is the fact that they may treat the negative symptoms as well as the positive symptoms. There are currently no FDA approved drugs for the negative symptoms of schizophrenia.’
Kappa Opioid Blockers as Treatments
The researchers argue that the kappa opioid receptors may be over-activated in people with schizophrenia, leading to changes in dopamine levels that cause too little activation in some parts of the brain but oversensitivity in others. These complex effects are proposed to underlie the range of different types of symptoms (i.e., the positive, negative, and cognitive symptoms). Dr Clark and colleagues suggest that by preventing this over-activation of the kappa opioid receptors, it is possible to treat more of the symptoms of schizophrenia than has been possible with existing pharmacological interventions.
Bringing together their work to date, Dr Clark and his colleagues have identified four different drugs that they believe will provide effective treatment: naloxone, naltrexone, nalmefene, and buprenorphine. As these drugs have already approved by the Food and Drug Administration (FDA) and the European Medicine Agency for use in other conditions, they have already been tested for safety, and naltrexone is currently widely available on prescription.
Dr Clark notes, ‘Amazingly, these drugs provide a large benefit above and beyond whichever antipsychotic therapy the patients are currently taking. Perhaps most importantly, is the fact that they may treat the negative symptoms as well as the positive symptoms. There are currently no FDA approved drugs for the negative symptoms of schizophrenia.’
Dr Clark and his colleagues are working to develop even better treatments for schizophrenia based on this research, with drugs in development that block just the kappa opioid receptors, in the hope that these can ameliorate the symptoms but without the side effects that occur when blocking the other two types of receptor.
‘We intend to use this model to not only finish the development of therapeutics which have been proven safe and effective, but also to setup a distributed collaboration network for the continued development of a steady stream of new therapeutics. Mental illness may be one of the greatest unmet medical needs facing us today and we hope to change this with our new model’
Benefits Beyond Schizophrenia
Dr Clark established Terran Biosciences Inc with the aim of optimising existing and developing new treatments for psychiatric illnesses by developing a worldwide collaboration of researchers and by applying a precision medicine approach to the development of new therapeutics. The approach of Terran Biosciences is different to the usual method of developing drugs in individual siloes of work as adopted typically by pharmaceutical companies. Instead, the focus is to use advanced diagnostic imaging and technologies such as patient specific organoid ‘minibrains’ to more specifically target the development of therapeutic drugs tailored to the patient’s unique symptoms. By taking a more targeted approach to developing drugs, the need for large financial returns is reduced and focus is placed instead on the need that a potential treatment could fulfil.
The benefits of this approach are readily apparent when considering the example of investigation into the kappa opioid receptor as a treatment target in schizophrenia. However, the aim of Terran Biosciences is to extend their work across the spectrum of psychiatric diseases. Dr Clark and his world class team conclude, ‘We intend to use this model to not only finish the development of therapeutics which have been proven safe and effective, but also to setup a distributed collaboration network for the continued development of a steady stream of new therapeutics. Mental illness may be one of the greatest unmet medical needs facing us today and we hope to change this with our new model.’
Meet the researcher
Dr Samuel Clark
Chief Executive Officer
Terran Biosciences Inc
New York, NY
Dr Samuel Clark completed his BS at the Massachusetts Institute of Technology, and MD and PhD at Columbia University, where his research focused on developing new methods for imaging the living brain. He pioneered the technique of using fluorescent false neurotransmitters (FFNs) in vivo as well as a new surgical technique (PHASOR) for multiphoton imaging of the living brain. With a focus in viral gene therapies, his research utilized a variety of viral vectors for gene therapy in the living mammalian brain. He has studied the kappa opioid receptor and explored its role in schizophrenia for over 11 years. Dr Clark is the founder and CEO of Terran Biosciences, a clinical stage biotech company which aims to transform the lives of patients with mental illness by applying precision medicine through patient specific organoid ‘minibrains’ to the development of novel neuropsychiatric therapeutics and medical devices.
Dr Anissa Abi-Dargham, Stony Brook University, USA
Dr Jared Van Snellenberg, Stony Brook University, USA
Dr David Pickar, Johns Hopkins Medical School and the Uniformed Services University of the Health Sciences, USA
Dr Ronald Marcus, Terran Biosciences, USA
S Clark, A Abi-Dargham, Dynorphin and the Kappa Opioid Receptor’s role in the symptomatology of Schizophrenia: A Review of the Evidence, 2019, doi: 10.1016/j.biopsych.2019.05.012.
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