Tag Archives: glutamate

New Antidepressants, at last

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New Antidepressant class: New mechanism of action

The Mandelbrot Set

Many unfortunate individuals suffer year after year of depression. Depressive illness becomes the defining feature of their lives, as one tablet after another fails, and the psychotherapies reveal themselves as blunt instruments.  For decades, psychopharmacologists have sought a new class of antidepressant, based on new mechanisms, rather those which target the brainstem-derived neuromodulators, serotonin, noradrenaline and dopamine. Finally, there has been a breakthrough. Ketamine, a molecule familiar to the anaesthetists, has repeatedly showed efficacy against stubborn depression. And recently, the s-enantiomer (esketamine) has been fast-tracked for clinical use in the USA after positive results in phase III trials. Ketamine necessitate intravenous administration, whereas esketamine, an intranasal spray, represents a much more practical option for wider clinical use.

The Neurophysiology: Extended consciousness, brain wiring & the personality

Ketamine blocks a receptor for glutamate, the main fast excitatory neurotransmitter in the cortex, thalamus and limbic system. This is the NMDA receptor channel, which is one of the most celebrated components in modern neuroscience, critical for short and long-term plasticity at glutamate excitatory synapses (Collingridge and Bliss, 1995).  Channel opening, and the inward flux of Ca2+, are the prime movers in boosting the strength of individual glutamate synapses, of which there are over 15,000 converging on a single neuron. Over the timeframe of seconds, NMDA receptor activation is essential for supporting conscious mental activity in the vast neural network (Ingram et al., 2018). NMDA receptor activation can also set in train processes which ultimately lead to the long-term structural enhancement of glutamate synapses, the basis for learning and memory. The personality is believed to emerge and develop as the neural network is sculpted and fine-tuned, at the level of individual synapses, by lived experience (Kandel, 1998)(DeFelipe, 2006).

Ketamine impacts upon the neural network, stimulating neurotrophic pathways and enriching neural connectivity, in keeping with the modern idea that depression stems from impoverished connectivity (McEwen et al., 2015).

nmda receptor
The NMDA Receptor.
Glutamate (GLU) and glycine (GLY) activate the NMDA receptor causing channel opening and influx of Na+ and Ca2+. Calcium is a second messenger which activates various from of plasticity. The NMDA receptor is a crucial starting point for working memory and epsiodic memory in the CNS.
Ketamine blocks the pore of the channel, impeding Na+ and Ca2+ influx.

The Psychophysiology: The complete transformation of lived experience & re-birth

Given the physiological importance of glutamate NMDA receptor channels for brain functioning, it is not surprising that ketamine, which blocks the channel pore and impedes the influx of Ca2+, has a profound effect on the psyche. Effects are dose-related. The anaesthetists make use of the fact that ketamine blocks conscious mental content, to the extent that surgical procedures can be carried out in otherwise awake patients, who can support their own respiration. Pain physicians also utilise ketamine, in the knowledge that chronic pain syndromes probably stem from an ingrained plastic adaptation in the cortical areas which support pain perception. For psychiatrists, there is range of ketamine doses which elicit such a complete transformation in lived experience, that some have labelled those experiences as psychotic. In fact, those experiences go much further the usual connotations of psychosis as hallucinations and delusions. Descriptions include, the cessation of time, the dissolution of the ego, near-death experiences and spiritual experiences, perhaps best demonstrated by the use of a plant-derived NMDA receptor channel blocker (ibogaine) as ceremonial entheogen in West Africa.

(There was hope and considerable investment in the idea that a new class of antipsychotic treatments, based on glutamate, could be developed, but this drug-discovery effort failed to materialise in end-stage trials. For depression however, the story has been much more encouraging, and the next phase is now unfolding.)

In West Africa, there is use of a plant-derived NMDA channel blocker called ibogaine. Ibogaine is in the same pharmacological class as ketamine. Ibogaine is used in tribal ceremony to transform conscious experience.

The Upside of NMDA channel blockers in depression

A number of clinical properties of NMDA channel blockers are highly favourable, in comparison to the older antidepressants. Above all, the NMDA channel blockers have a very rapid impact upon depression, within hours, compared to several weeks for the older drugs. The NMDA channel blockers can also impact upon the most stubborn depressions, in which the older drugs, psychotherapy and even ECT proved ineffective and frustrating. Finally, the NMDA channel blockers have a rapid anti-suicidal effect, which as experience accrues, may come to represent a specific indication in acute settings.

The downsides: NMDA channel blockers in depression: Real, potential & hyped

All effective treatments carry a downside in terms of side effects, but in comparison to much older psychiatric therapies such as clozapine, lithium and benzodiazepenes, ketamine/esketamine are remarkably safe. Of course, many patients will be put off by the idea of having psychedelic experiences and there is also a worry over possible diversion, given that ketamine is used as a club drug by people actually seeking those very same psychedelic experiences. Compared to other drugs of abuse however, ketamine addiction is a rare phenomenon, and withdrawal reactions are not recognised. Heavy, unrestrained use of ketamine is known to cause bladder dysfunction, but this appears to be a feature of recreational misuse rather than in the clinic, where bladder function can easily be monitored. 

It has been suggested that ketamine works in the same way as an opiate. Naturally this has led to scare stories, given the recent experience of opiate prescribing in the USA. However, the psychopharmacology of ketamine and opiates are quite different at the behavioural and molecular level. The most serious adverse effect of opiates is respiratory depression and death, because of overstimulation of mu receptors. Ketamine, an NMDA receptor channel blocker, does not cause respiratory depression, and the analgesic effects of ketamine in the CNS do not appear to be mediated via mu opiate receptors. 

Perhaps the major downside of NMDA channel blockers is that the antidepressant effects typically diminish after about one week. With repeated sessions, this can be extended to about three-four weeks. A major challenge for psychopharmacologists is how to extend the duration of the antidepressant effect. In the UK, ketamine treatment for depression has been available at the NHS Warneford hospital in Oxford for about a decade.  Many patients who benefitted from an initial course of intravenous ketamine return for maintenance sessions, in which the gap between sessions is individually tailored. These are patients whose lives were hitherto dominated by depression, and who found no relief from standard approaches. With maintenance treatment, they can enjoy depression free lives. Hopefully, the time-limited nature of the antidepressant effect will eventually be understood and solutions developed.

Esketamine, as an intranasal spray, now offers the possibility of more widespread and perhaps even routine clinical use for many others disabled by clinical depression. Although there are concerns, it should be realised that the prescribing of NMDA channel blockers will take place within a therapeutic relationship in which close attention is paid to how an individual patient responds, the swift recognition of any adverse effects and provision of supportive psychotherapy (and perhaps in time, even a specialised adjuvant psychotherapy). Measures to prevent diversion can be put be put in place.

History Repeats: A new Golden Age of Psychopharmacology

The old tricyclic antidepressants translated into the clinic within three years of the first positive findings in 1957, in what has been termed the Golden age of Psychopharmacology. Aside from the benefits to thousands of individual patients, a new era of neuroscience was initiated, which revealed much of the physiology of serotonin and noradrenaline (Leiberman,, 2015). Over the ensuing decades, the basic science of brainstem derived neuromodulators and monoamine-based therapeutics developed in tandem, leading to the development of safer alternatives, (the SSRIs in 1971). The positive findings with ketamine and esketamine in depression are ushering in a similar scenario. This time of course, the tools of molecular neuroscience are available, so that the pace of discovery should be quicker, and at a much more fundamental level. Already the therapeutic benefits of NMDA channel blockers are being made available for patients whose lives have been dominated by depression. Just as happened for the older antidepressants, refinements will be made over the coming years with the joint efforts of laboratory based pharmacologists and psychiatrists who treat depressed patients. Novel administration regimes, adjuvant psychotherapies, and new candidate molecules targeting other components of glutamate neurotransmission are likely to appear.

Collingridge GL and Bliss TVP (1995) Memories of NMDA receptors and LTP. Trends in Neurosciences18(2): 54–56. DOI: 10.1016/0166-2236(95)80016-U.

DeFelipe J (2006) Brain plasticity and mental processes: Cajal again. Nature Reviews. Neuroscience7(10): 811–817. DOI: 10.1038/nrn2005.

Ingram R, Kang H, Lightman S, et al. (2018) Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity. Neuropharmacology142: 30–40. DOI: 10.1016/j.neuropharm.2018.06.008.

Kandel ER (1998) A new intellectual framework for psychiatry. The American Journal of Psychiatry155(4): 457–469. DOI: 10.1176/ajp.155.4.457.

Lieberman JA (2015) Shrinks: The Untold Story of Psychiatry. New York: Little Brown and Company.

McEwen BS, Bowles NP, Gray JD, et al. (2015) Mechanisms of stress in the brain. Nature Neuroscience18(10): 1353–1363. DOI: 10.1038/nn.4086.

Psychiatric illness ‘explained’: Disorders of CNS Connectivity

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The power of the nervous system:

network-of-cortical-neurons

The astonishing power of the nervous system does not reside in a single neuron. (That said, an advanced supercomputer is required for the task of modelling the processing power of even a single neuron).

Nervous tissue is immensely powerful because of the rich connectivity between neurons. A 1mm voxel of cerebral cortex (a standard fMRI unit), contains ~300 million synaptic connections and ~50 thousand neurons [ref].  Scaled up to the whole human brain, there are estimated to be several hundred trillion synaptic connections within a total pool of ~100 billion neurons. Neuronal networks are the foundation of, perception, movement, thinking, memory and the personality.

Network learning

A crucial property of neuronal networks is that they learn from experience. Experience may stem from the external world (sensation) or the inner world. Learning is achieved by adjusting the strength of the connections between neurons. New connections can form, and weak connections wither away – essentially a process of re-wiring. Taking up a musical instrument or a new language, for example, constitutes a major re-wiring exercise, although higher, more mysterious faculties – such as selfhood, agency and individual identity – are already wired-up in infancy, and remain a foundation throughout life, except if threatened by the most severe psychiatric disorders.

Alzheimer’s disease is the prototypical example of a network illness. Progressive       shrivelling of the network mirrors the decline of the faculties, from initial problems with memory right up to the disintegration of selfhood.

Network health

Network health is vital for mental health. The stabilisation of essential connections, the formation of new connections and the controlled elimination of redundant connections involves many components.

  • There are components which span the gap between nerve terminals and dendritic spines to ensure that connections remain tightly bound [link].
  • There are signalling pathways which control the dynamic, flexible actin scaffold which give terminals and spines their anatomical structure.
  • There is, ready-to-hand, protein-synthesis machinery for making additional spines as learning proceeds.
  • Finally, and most recently explored, there are mechanisms for ‘clearing up’ the debris when connections are no longer required. Such components (microglia, complement proteins) are much more familiar in their role as immune cells and immune signals, but their role extends beyond inflammation. Microglia and complement are now recognised as key components in the wiring of the brain as it learns and develops.

Major psychiatric illness

dendritic spine

Where those components involved in the function and structure of synaptic connections are defective, psychiatric illness can result. Mutations in the components which bind the nerve terminal and dendritic spine are a cause of autism. The cause of many learning disability cases, hitherto unknown, are mutations in proteins which control the actin scaffold. The psychiatric manifestations of Fragile X syndrome (intellectual deficits / autistic features / hyperactivity) result from abnormal protein synthesis in dendritic spines and subsequent abnormal local wiring.

dendritic-spine

Microglia & complement proteins

pink-eatme-cake-topperThe latest components to receive attention, as pertains to psychiatric illness are the microglia and their signalling pathways, specifically complement proteins.

Complement proteins function as a tag, essentially an ‘eat-me’ signal, on synapses destined for elimination. The tag is recognised by the phagocytic microglia which engulf and clear the redundant synaptic elements [link].

Although the role of immune components in psychiatric illness has become a hot topic, many researchers are still accustomed to regard microglia and complement in the context of inflammation rather than CNS re-wiring. Both major depression and schizophrenia, have been linked with abnormal immune components, but neither disorder is inflammatory in the same sense as encephalitis or meningitis. The main histological finding in schizophrenia is decreased connectivity between neurons, not inflamed nervous tissue. Similarly, an anatomical correlate of depression is impoverished connectivity in the hippocampus, not inflammation.

A major development in Alzheimer’s research has been the recognition of up-regulated complement proteins and microglial phagocytosis commensurate with the loss of neuronal connections. The crucial observation is that such changes occur prior to amyloid deposition and tangle formation [link]. Alzheimer’s appears to be a disorder of runaway synaptic loss. Drug discovery efforts are aimed at blocking complement protein receptors to protect synapses [link].

Schizophrenia has been associated with changes in the genes coding for a specific complement protein (C4A). Knockout of the C4A gene in an animal model causes a marked alteration in the pruning of synaptic connections in later life [link]. Schizophrenia, albeit to a far less extent than Alzheimer’s, is regarded as a disorder of impoverished connectivity, (whereas Autism is associated with increased dendritic spines and increased connectivity) [link].

Hold on –  what about the ‘dominant’ wet-ware hypotheses?

hoovers

An older generation of psychiatric researchers may ask where dopamine [link]] and perhaps glutamate [link] fit into a model of psychiatric illness in which abnormal connectivity between neurons appears to carry robust explanatory power. Earlier models posited that an excess or deficiency of neurotransmitter or receptors lay at the root of major depression and schizophrenia. Such models stemmed from the relatively primitive knowledge of the synapse available at the time (circa 1965-1975). Then, the hot topics in neuroscience were; the nature of neurotransmitter release (Sir Bernard Katz, UCL) and the ‘visualisation’ of receptors (Solomon Snyder, John Hopkins).

The answer (to the question of how glutamate and dopamine are accommodated) is fairly straightforward: Glutamate (finally admitted to the neurotransmitter club circa 1983-87) is the fast neurotransmitter between nerve terminals and dendritic spines, throughout nervous tissue. Dopamine determines the strength of the connection between the glutamate terminal and the dendritic spine within specific CNS structures. Dopamine functions as a teaching signal; adjusting connectivity and promoting learning in higher centres.

Frontier psychiatry

hippocampus

The obvious strategy of searching for molecules which can impact on connectivity is well underway.

That said, existing psychiatric treatments, such as antidepressants, lithium and dopamine antipsychotics have an impact upon connectivity to the extent that structural changes can already be detected, albeit in a population of patients rather than the individual, with routine MRI scans. Drugs impact upon plasticity: Drugs impact upon CNS structure.

A more basic question goes back to the very roots of modern psychiatry. The question is whether, for some, the neuronal networks are destined to be unwell from the outset (endogenous psychiatric illness), or if, for others, adverse experiences during development cause the network to wire-up pathologically (exogenous psychiatric illness). Then again, there is the third position, in which the choreography between the neuronal hardware and the external environment determines who will succumb to psychiatric syndromes. Whatever the proximal cause(s), endogenous or exogenous, major psychiatric illness appears to stem from abnormal connectivity within neuronal networks.

Trendy Psychiatric Research: A need to sanitise hubris and bad faith?

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An article in the Times by Dorothy Bishop explores some of the problems in biomedical research which arise from the obsession with high-impact journals and expensive grants.

monopoly boardHer critique is especially apt in the case of the physical basis of mental illness, in which researchers seeking fame and fortune must master the storytelling arts of simplicity, metaphor and metonymy. Those seeking H-impact & lucre must stay “on message” and above all, never stray into the chaos of imperfect methods and noisy data.

 

http://www.timeshighereducation.co.uk/comment/opinion/the-big-grants-the-big-papers-are-we-missing-something/2017894.article#pq=M87JTT

Bishop concludes with a warning, that the relentless focus on publishing in prestigious journals encourages…

1. Over-claiming the significance of research findings.

2. Leaving important, but contradictory results unpublished.

Hubris is the orientation of the former, bad faith the foundation of the latter.

“…what changes everything is the fact that in bad faith it is from myself that I am hiding the truth“. http://www.philosophymagazine.com/others/MO_Sartre_BadFaith.html

Why NMDA drugs keep failing in schizophrenia.

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nmda receptor

The NMDA receptor. Glutamate and glycine are required for NMDA receptor activation. Activation involves the opening of a channel allowing calcium and sodium ions to flow into the neuron. Recent attempts to translate NMDA pharmacology into the clinic have focussed on the glycine site.

Twenty years ago it all looked so promising. The model was as follows: Learning and memory were clearly being driven by activity at the glutamate NMDA receptor. Boost the NMDA receptor by pharmacological means, and perhaps intellectual performance could be improved above baseline. The hope was that an NMDA enhancer might work in schizophrenia, which many had come to regard as a disorder of cognition. Yet the story has not played out as anticipated. The latest generation of NMDA enhancers, like their predecessors, has failed in schizophrenia [link]. And it is looking increasingly likely that the basic model [boost NMDA -> boost intellectual functioning] was overtly simplistic.

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

An recent review article by Collingridge and colleagues is worthy of study. Back in 1983, Collingridge had shown that activation of the glutamate NMDA receptor was the initial catalyst for the process of LTP (long-term-potentiation). At that time glutamate was only just gaining entry to the neurotransmitter club, whereas LTP [a process in which excitatory synapses become and remain stronger] had achieved fame ten years earlier as a likely substrate for learning and memory in nervous systems.

The discovery of NMDA-dependent LTP, as the phenomena came to be known, was the stimulus for an enormous, worldwide research effort into glutamate neurobiology. Since then, our knowledge of NMDA receptors has advanced, to the point where the complexity can be overwhelming [figure below]. But the medicines have not materialised. The biology appears to be several orders more complex than the model. Is that why the drugs have failed? In any case, the model [boost NMDA -> boost intellectual functioning] can now be safely abandoned with little risk of missing a major therapeutic breakthrough.

Intracellular modulation of NMDA receptors

Sites of intracellular modulation of NMDARs. Schematic representation of the distribution of selected posttranslational regulatory sites on the intracellular C-terminal domains of NMDAR subunits. Properties such as channel gating, receptor desensitisation and receptor shuttling are modulated by phosphorylation at key residues. Collingridge et al 2013

POSTSCRIPT

Recently the NIMH (National Institute of Mental Health], the main funder of mental health research in the world, announced that they would no longer support clinical trials of new drugs unless there was a clear mechanistic advance at the same time:

“a positive result will require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation.”

The NMDA receptor story calls the logic of this approach into question. That story is the archetypal case in which a mechanism was clearly defined, and well supported after decades of preclinical research. Indeed the mechanism [the model] had become so appealing that many were reluctant to abandon it, even as it was becoming obvious that the therapeutics were not going to work. An overhaul of drug discovery in psychiatry is needed, but it will require to be more realistic than solving mechanism and efficacy problems concurrently. Pulling back the bureaucracy, the inflated costs and the micromanagement could be a more fruitful intervention.

Ketamine for resistant depression: Outstanding promise, outstanding issues.

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Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it's powerful antidepressant properties (Berman et al 2000; Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it's beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism

Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).