Treatment Resistant Depression: future prospects

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

The power of the nervous system:


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.


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?


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


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.

Next-generation, evidence-based healthcare management

barnsleyfernHealthcare delivery is at last beginning to adopt mathematical and engineering principles [link]. There is an awareness, especially in the USA, that the leadership of an inherently chaotic system requires a professional mathematical sensibility, infinitely more sophisticated than the tired mix of power-point, polished-comportment, faux-bonhomie, affected-positivity and sloganeering.

Complex systems are made up of many components. A decision which impacts upon one component in a healthcare system may affect other components, and indeed the whole system, in a way which was not predicted at the outset. Quite often a decision aimed at conservation can actually end up leaking resource as unforeseen consequences on the whole system emerge.

Mathematical modelling of complex systems, such as a healthcare trust, can provide insight into how the change in one component affects other parts of the system. With a deeper analysis of the system, decisions can be taken with less uncertainty over downstream consequences.

Healthcare delivery services and their administrative and managerial supports are recognised as complex adaptive systems. Adaption signifies that the system learns from feedback and moves, overtime, ever closer towards an optimal configuration. Systems differ in their adaptiveness, however. Some evolve, almost effortlessly, towards an optimal configuration, but others appear to move chaotically from one state to another. The perception is that healthcare delivery in the UK typifies the latter.

Mathematical modelling is the ideal method for guiding healthcare delivery systems towards an optimal configuration. It is suggested that the optimal configuration of a healthcare system is aligned with the principle of utilitarianism;

Maximal well-being for a maximal number, at minimal cost.

Cannabidiol (CBD) softens the effect of THC (again).

DataRemixed-Logo45Congratulations to Dave Nutt, Val Curran and their colleagues at Imperial and UCL. Following on from their groundbreaking studies of MDMA on channel 4, they have now repeated the same format with cannabis.

Running live psychopharmacology studies on television is not for the faint hearted, but it offers a unique way to impart public health knowledge in a way which is lively and captures the imagination. And the visual element works well.

The personal testimony of Jon Snow and the other participants was particularly revealing. The channel 4 experiments on cannabis demonstrated that CBD can inhibit the tendency for THC to produce paranoid thinking, a finding that was in complete agreement with two previous studies at the Institute of Psychiatry a few years back.

1. Does CBD inhibit THC?
2. Cannabidiol inhibits THC-elicited paranoid symptoms

All the evidence points in the same direction, skunk cannabis [high THC, zero CBD] is more hazardous for mental health than traditional cannabis [equivalent CBD & THC]. The community-based studies in psychiatric clinics and the experimental studies in the lab are in complete agreement on this point [link]. CBD softens the effect of THC again and again.

Holding up Psychiatric Progress – the new Bureaucrats.

Psychiatric research ultimately aims at improving the wellbeing of those who suffer from mental illness. In its purest form, the momentum for this effort comes from a desire to relieve the inner crisis of another person, rather than for personal glory or for trumpeting the ‘impact’ of a particular university in the international market. It is irrelevant where a genuine breakthrough occurs, or who achieves it, if the collective desire is to enhance our technical ability to relieve mental suffering in our fellow man.

orson welles 1962

The momentum of psychiatric research is being stalled by the amount of paperwork required to satisfy the plethora of new bureaucrats employed in paperwork governance.

And yet the natural flow of this altruistic endeavour is being stymied by an ever-growing, self-serving uber-bureaucracy within British Universities. Research looking for better treatments, which would once have been up and running within a month or so, is now required to jump through numerous, seemingly arbitrary, local hoops.

In the UK, the new bureaucracies have tagged themselves onto the longstanding [and highly commendable] ethics process. But whereas the ethics committee rightly puts the patient and patient safety above all, these new regulatory bodies have little concern with the patient or with medical science. Their only concern is governance of the paperwork – wrong form, wrong version number, needs additional sign off etc. – driven perhaps by the fear of an inspection by another bureaucratic body, higher up the bureaucratic food-chain, and so on.

The new bureaucrats show their mastery of the arts of pedantry in those cases where the researchers believe that the protocol could benefit from a subtle amendment; for example, a request to roll out the availability of a promising new treatment to a wider geographic area. But at this juncture the uninitiated young researcher should prepare for interminable delay, much cross-checking of documents, submissions, gentle scoldings and re-submissions! Eventually, hopefully that happy day will come, [ideally before the end of their university contract or the drug-expiry date], when the paperwork has met the stringent demands of the local apparatchiks, and can finally be presented for a re-hearing at the ethics committee proper – who usually pass it that same day without fuss.

The real sadness is that the University bureaucrats recoil instinctively from the creative solution, the quick-fix, even if it is aimed at “helping to speed up the development of new treatments“, to borrow the typical phraseology from the ever-expanding media office [another growth area in our Universities and hospitals]. It is also of little use in explaining to the bureaucrat that experimental therapeutics proceeds in a trial and error fashion, and that flexibility is to be desired in the interests of progress, as evidenced by the history of clinical psychopharmacology [and medicine as a whole]. The naivety is the hope of working together with the bureaucrat, to find a quick solution. But the bureaucrat cannot move away from procedure. The bureaucrat is inflexible at all times, in all situations, by definition.

So the new reality is that paperwork governance has become more powerful than the medical science it was originally set up to support. Reform is needed, mainly for the sake of those patients who continue to suffer from psychiatric disorders and who don’t get better with existing treatments. The stalling of progress in psychiatric therapeutics, the stalling of hope, not on grounds of concern for participants or because of technical risk, but rather on arbitrary, locally-set, self-serving bureaucratic grounds, is an affront to those patients – and has reached the threshold of being an ethical issue in itself.

Oscar Wilde — ‘The bureaucracy is expanding to meet the needs of the expanding bureaucracy.’