Monthly Archives: March 2013

Dopamine & psychosis: Old fashions, new findings.

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Dopamine is the archetypal late '60s, early '70s transmitter, famous for it's involvement in schizophrenia. Like much else from this era, the dopamine story is discovered anew by successive generations. That story – that the dramatic symptoms of schizophrenia are caused by too much dopamine – has survived as fashions have come and gone.

dopamine terminal

Dopamine is synthesised in pre-synaptic boutons from the amino-acid tyrosine (TYR), via DOPA. Patients who respond well to anti-psychotics appear to have increased synthesis of dopamine (DA).

A recent paper from researchers in London adds a new twist. It appears that those patients who respond well to anti-psychotic drugs (which block dopamine receptors) have elevated pre-synaptic dopamine. In contrast, the (thankfully small) group of patients who don't do so well on anti-psychotics appear to be no different from healthy controls in regard to pre-synaptic dopamine.

Further work, including replication of the findings, will be necessary. But these results suggest that there are dopamine and non-dopamine forms of psychosis.

Hopefully, in time, there will be technological improvements allowing prospective testing of individual patients prior to initiating drug therapy. New, non-dopamine based anti-psychotics are also a priority.

The abstract can be read here

Download a free high-res vector graphic.

Cool Memories: The Recurring Crisis of Psychiatry.

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The diagnostic system for delineating psychiatric disorders ('The DSM') is in it's fifth rewrite. It had been anticipated that advances in fMRI imaging and molecular genetics would have finally put psychiatric diagnoses on a medical footing. Alas fMRI has failed to live up to it's promise. And genetics, if anything, has been too powerful – by toppling the whole framework of DSM.

A new paper by Juan & Maria-Ines Lopez-Ibor captures the zeitgeist, but also reveals that the current debates and controversies are nothing new. For over 150 years, psychiatry/psychology has struggled to establish itself as a natural science because of three major issues – 1. Classification difficulties. 2. The mind-brain duality problem. 3. The perils of phrenology (localisationism).

[The full paper can be read here].

These issues have been acknowledged many times before, but never as a collective – and perhaps never as elegantly (even with some minor errors of translation from Spanish into English).

On classification…

“Psychopathological phenomena certainly exist and can be observed and experienced as such. However, psychiatric diagnoses are arbitrarily defined and do not exist in the same sense as psychopathological phenomena do”.

On dualism…

“Dualism manifests itself in the separation of mental and physical diseases, of psychiatry and the rest of medicine, of neuroses and psychosis, of biological research and interventions from other psychosocial approaches and in the proliferation of psychiatric sub-disciplines”.

& on phrenology (localisationism)…

“A phrenological approach still survives in neurological and psychiatric research…This approach has been extended to the neuropharmacology attributing specific neurotransmitters psychological functions”.

The text may be gloomy, for some. Others may engage in playful delight at references to Plato, Greisinger and the Upanishads. A follow up paper is in press (this was part 1), and much is promised…

“Modern science and modern medicine are, no doubt, the greatest achievements of humankind having change for the better of millions of human beings. We are not arguing to throw the baby with the water in the tub, but to look for fresh water to replace or replenish the existing one. This we will do in the second part of this article”.

 

NMDA receptor encephalitis: An acute organic psychosis.

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Mental health clinicians should be mindful that numerous physical illnesses can present with psychiatric symptoms. A case in point is a recently described autoimmune disorder in which antibodies target glutamate NMDA receptors within the brain. Acute psychosis and cognitive dysfunction are so prominent in this condition, Anti-NMDA receptor encephalitis, that many patients are initially referred to psychiatry. Swift and accurate diagnosis is essential, as the appropriate therapy is immunological rather than psychiatric.

The antibody targets the extra-cellular portion of the NMDA receptor. Initially, there is an increase of NMDA mediated currents. But hypofunction emerges, the receptor appears to be internalised and vital functions such as long-term potentiation (LTP), which are essential for cognition, are lost. [see link]

Anti-NMDA receptor encephalitis

Symptoms and signs

Anti-NMDA receptor encephalitis was first described in young women with underlying ovarian tumours. But cases in males, in children and non-tumour cases are well documented. In about 20% of presentations, neuropsychiatric symptoms are preceded by a flu-like illness. Early symptoms in adults are psychosis (hallucinations, delusions and bizarre behaviour), cognitive impairment (confusion, memory dysfunction, dysphasia), and seizures. Over days to weeks additional neuropsychiatric features emerge; movement disorder (choreoathetoid, myoclonus, parkinsonism, rigidity), autonomic instability (tachy/bradycardia, labile BP, hypersalivation, central hypoventilation) and reduced levels of consciousness [full paper].

Investigations

In terms of investigation, CSF lymphocytosis, CSF oligoclonal bands, EEG slowing and epileptiform potentials can be found. The MRI scan is usually normal. The diagnosis is clinched by the presence of CSF IgG antibodies against the NR1 subunit of the NMDA receptor.

Treatment

The treatment of choice is immunotherapy (IV steroids, IV immunoglobulin, plasma exchange) – as well as tumour resection. A good outcome is associated with a decrease in NMDA receptor antibody levels. In some patients the recovery is prolonged, and 2nd line immunotherapies are required. Interestingly, many patients have also responded well to modified ECT.

NMDA receptor autoantibodies & Schizophrenia?

There has been recent interest in the possibility that many cases of diagnosed schizophrenia may actually be alternative forms of anti-NMDA receptor encephalitis. But the evidence for this is not convincing. In a Spanish study of 80 patients, no cases were positive for anti-NMDA receptor IgG antibodies. In a larger study from Germany (approx 450 acute patients), there was an excess of anti-NMDA receptor antibodies in acute schizophrenia (10%) versus major depression (3%). But these were not the IgG antibodies against the NR1 subunit, which is the defining feature of NMDA receptor encephalitis. Instead there were IgA and IgM antibodies against the NR1 and NR2 subunits. The significance of these antibodies is not entirely clear, especially as they were also found in healthy controls (0.4%). Are they a marker of a prior insult against the NMDA receptor or an incidental finding? – A question which will now attract much research.

 

Cognitive disorders: the role of dendritic spines.

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Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be 'absorbed' back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are 'pruned' back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer's and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.

Regulation of the spine:

The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHO family. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to 'coalesce' at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it's complexity (and beauty).