Tag Archives: major depressive disorder

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 genetics: everything you need to know.

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Psychiatric geneticsPsychiatric genetics can be daunting for the non-expert. But it is so important for all mental health researchers and clinicians to have some understanding of where this field is at. Unlike much of the rest of psychiatric research and theory, modern genetics represents a firm foundation of valid and reliable knowledge. That knowledge is slowly unfurling how we think about psychiatric disorders such as ADHD, autism, depression, OCD, substance abuse, schizophrenia and bipolar.

A 2018 paper by Kendler and colleagues is an ideal overview, a straightforward, highly readable account of where things stand in psychiatric genetics, put in a historical context.

It has long been known that psychiatric illness runs in families. The heritability of psychiatric disorders (i.e. the degree of variance in a trait in a population which can be explained by genetics alone; a figure between 0 and 1) ranges from 0.3-0.4 for PTSD and depression, up to 0.7-0.8 for ADHD, autism, schizophrenia and bipolar. (Figure 1. Orange diagonal).

Psychiatric genetics

For the more genetic disorders (ADHD etc.) susceptibility very rarely comes down to one gene. Far more commonly, hundreds of individual genes are involved. Each gene, on its own, carries a tiny, almost negligible effect, at least in clinical if not statistical terms. But when a collection of risk genes is inherited, the chance of developing a psychiatric disorder starts to increase. For experts in psychiatric genetics, this is known as the polygenic risk score (PRS) the summed value of all the individual risk genes. The PRS is an important measure in modern psychiatric genetics.

Another important key-word is pleiotropy. This is when the same gene is involved in more than one psychiatric disorder. Pleiotropy has been recognized in psychiatry for some years. For example, a gene coding for a Ca2+ channel found on neurons, has long been known to constitute risk for a range of psychiatric disorders such as schizophrenia, bipolar, autism and major depression. Such knowledge is increasingly challenging the long-held view that there are discrete, neatly demarcated psychiatric disorders, as is found in the DSM and ICD classification systems.

Genetics researchers are now turning their attention to how a collection of genetic variants that increase the chances for one disorder (the polygenic risk score, PRS) may also increase the risk for other psychiatric disorders. This is pleiotropy at a higher level. The early findings again point to crossover between disorders. Kendler and colleagues elegantly illustrate the headline findings (Figure 1). The light blue squares show the genetic correlation between disorders using the methods of modern molecular genetics. The light orange squares show the genetic correlation between disorders using the more historical methods of family and twin studies.

For the present the main research effort will be to gather and pool more whole genome data from individual patients (and controls). Sample sizes of >100,000 will find more and more gene variants which confer risk for psychiatric disorders. Groups such as the multinational psychiatric genomics consortium (PGC) co-ordinate this task. Data-sets and computing resources are freely available to any researcher. Whether the traditional diagnostic systems collapse completely or remain in a different form cannot be know at present, but with modern molecular genetics, psychiatry is at last on a firm empirical and theoretical ground.

Treatment Resistant Depression: future prospects

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Many patients go through years and years of depression which stubbornly resists treatment. Therapy, SSRIs, even ECT, can all fail to provide any shift.

But a recent paper by Oxford psychiatrist Phil Cowen brings some light. In a readable and straightforward account, Cowen weighs-up the various options that are available, when first and second line antidepressant treatments are ineffective.

Depressed patients, GPs and psychiatrists will find the text very useful in selecting options – and in keeping hope alive. Topics covered include various combination and augmentation strategies and their statistical likelihood of success. Also, an expert appraisal of several new approaches, which are showing promise – including ketamine and psilocybin. Recent findings with pramipexole, a drug already used in neurology, are especially encouraging.

The full text published in the journal Psychological Medicine is available here.

 

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.

Zapping the Blues: The effectiveness of magnetic and electrical stimulation for treatment-resistant depression.

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Blake glad day

Treatment-resistant depression (TRD) affects 1-3% of the population. Recently Holtzheimer & Mayberg reviewed the effectiveness of a range of new and promising techniques based on direct neural stimulation. The list includes Transcranial magnetic stimulation, Transcranial direct current stimulation, Magnetic seizure therapy, Vagus nerve stimulation and Deep brain stimulation.

The prototype of course is ECT (electroconvulsive therapy), which is a highly effective treatment for melancholic depression, but suffers from the effects of a negative historical portrayal. The authors present a balanced and elegant appraisal of the current state of affairs for the new techniques which can be read here in full. The summary points are as follows…

Transcranial magnetic stimulation (TCMS)

– FDA (US food & drug administration) approved.

– Uses rapidly alternating magnetic fields to induce current in the underlying cortex.

– 10 to 30 treatment sessions over 2-6 weeks.

– Controlled trials have been positive.

– Response rates in TRD: 20-40%.

– Remission rates in TRD: 10-20%.

– Repeated courses may maintain initial benefits.

Transcranial direct current stimulation

– Delivers a low-intensity direct current to the underlying cortex.

– 5 times per week treatments for several weeks.

– Fewer side effects than TCMS?

– Antidepressant effects claimed from a small number of open and controlled studies.

– Response, remission & relapse rates are unclear.

Magnetic seizure therapy

– Seizures are induced using a transcranial magnetic stimulation device.

– Antidepressant effects from a small number of open studies.

– Claims for less side-effects than ECT, but may be less effective.

Vagus nerve stimulation

– FDA (US food & drug administration) approved.

– Electrical stimulation to the left vagus nerve through an implanted pulse generator.

– Open-label response rates in TRD: 30-40%.

– Open-label remission rates in TRD: 15-17%.

– No evidence for efficacy in a large controlled study.

– Simple surgical procedure.

Deep brain stimulation.

– Precise neurosurgical implantation of electrodes using stereotactic techniques.

– Remission rates in TRD: 40-60%.

– Relapse in remitted patients is uncommon.

– Complex surgical procedure.

Holtzheimer & Mayberg conclude, “Neuromodulation for depression is at an exciting and promising stage of development, and continued well-conducted research will help clarify and realize its potential“.