Tag Archives: schizophrenia

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).

 

Major mental illness and the Love hormone

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Oxytocin for schizophrenia – More positive news

Oxytocin is a hypothalamic peptide which is involved in social cognition and social behaviour. It is sometimes colloquially referred to as the 'love hormone', given it's involvement in bonding, empathy and trust. In recent years, oxytocin has been proposed as a possible new treatment for psychiatric disorders in which inter-personal relationships are problematic. The list of candidate conditions has included social anxiety disorder, autism and schizophrenia.

In the case of schizophrenia, clinical trials have begun to appear in the last few years. Two American groups have reported promising findings in small-scale studies. New findings from a trial carried out by researchers based in Tehran are also positive. The Iranian trial has the advantage in that patients were followed up for 8 weeks, compared to 2-3 weeks in the US studies. It was also slightly larger in size.

In the Iranian study, the addition of oxytocin to risperidone led to improvements in the intensity of positive psychotic symptoms (hallucinations, delusions and suspiciousness). There were also improvements in negative symptoms (apathy, amotivation, reduced sociability), although this was less pronounced.

The authors concluded: “Oxytocin as an adjunct to risperidone tolerably and efficaciously improves positive symptoms of schizophrenia. In addition, effects on negative and total psychopathology scores were statistically significant, but likely to be clinically insignificant. The interesting findings from the present pilot study need further replication in a larger population of patients.“

The paper is available here

 

New treatments for schizophrenia?

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The 1st generation anti-psychotics

It is sometimes said that all the treatments in psychiatry were discovered by chance (or serendipity, to use the technical term), rather than by planning. This is not strictly true. In fact many of our treatments for schizophrenia were discovered by design. The rationale was to start with a molecule which could induce a transient psychosis, even in healthy people – a molecule like amphetamine or LSD.

Thereafter the task was to find a drug which could block the effects of the psychosis-inducing compound. Such a drug, it was reasoned, could be an effective medicine for schizophrenia.

A Belgian researcher called Paul Janssen used this approach to great effect. He observed the effects of amphetamine in professional cyclists, who were using the drug to combat fatigue. Many of the cyclists developed an acute psychosis which was identical to paranoid schizophrenia. Janssen was the owner of a private research facility and was in an ideal position to search for medicines which could block amphetamine.

Progress was rapid and the compound haloperidol was discovered. And it turned out that haloperidol was a highly effective medicine for schizophrenic psychoses. Used in small doses, without interruption, haloperidol is a powerful treatment against hallucinations, delusions and agitation. But high doses are best avoided, as they can cause movement disorder.

The 2nd generation anti-psychotics

With this success of haloperidol, attention focused on other psychosis inducing drugs. This time LSD was taken as the psychosis-inducing agent. Numerous reports had shown that LSD (or 'acid') could transform consciousness in a way which was similar to the experience of people with schizophrenia. What was needed was a compound to block LSD, followed by a trial of the new compound in people with schizophrenia. Again the approach worked, giving us the medicine risperidone.

Olanzapine, sertindole, quetiapine and others followed. This class of anti-psychotic has become the first-line treatment in many countries and carries much less propensity to cause movement disorder as a side effect. However, careful attention is needed to avoid problems of weight gain and high cholesterol. Haloperidol acts on the dopamine system whereas second generation anti-psychotics like risperidone work on dopamine, but also target another brain transmitter called serotonin.

The next generation anti-psychotics

Two other drugs of abuse are associated with psychotic reactions. The first of these is ketamine, which has become popular on the club scene. Ketamine can elicit bizarre changes in consciousness which resemble the picture of schizophrenic psychosis. Ketamine can also induce the so-called negative symptoms. (Apathy, loss of drive and a reduced capacity for emotions, along with a rigid, concrete style of thinking).

The glutamate NMDA channel. Ketamine blocks the channel. Drugs which counteract ketamine may be useful antipsychotic medicines.

 

Ketamine works on the glutamate signalling system. As before the task was to find a compound which blocked the effects of ketamine. This has now been done, and in fact there are several different types of molecule available (Bitopertin, AMG747).

Now the challenge is to assess if any of these new compounds are good treatments for schizophrenia. At this time, several clinical trials in schizophrenic patients are underway, including some at The Institute of Psychiatry in London.

The other promising lead involves compounds which can block the effects of cannabis. About a dozen recent studies have shown that repeated use of cannabis is a risk factor for the development of schizophrenia. Skunk cannabis is known to be particularly hazardous for mental health. (Skunk contains high THC).

THC acts at cannabinoid receptors. Drugs which block the effects of THC are showing promise as medicines for schizophrenia.

 

Our research group and others have shown that a natural molecule called CBD can oppose the effects of THC in humans. CBD therefore becomes a candidate anti-psychotic medicine. Already one trial in Germany has found CBD to be as effective as a second generation anti-psychotic in people with schizophrenia. A number of larger studies are now underway. For an svg image click here.

 

Summary

There is an ongoing search for new medicines in schizophrenia. The first compounds such as haloperidol led to a fundamental change in psychiatric practice. The second generation medicines 'solved' the problem of motor side-effects, but at the cost of obesity and other metabolic complications. Hopefully a new generation of effective anti-psychotics will emerge in the next few years. Like their predecessors, the roots of their development may well be in design rather than by chance.