Understanding schizophrenia 1: What exactly is schizophrenia?

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The Royal Bethlem psychiatric hospitalSchizophrenia has long been the heartland of psychiatry, but can be as confusing now as it was 100 years ago. Lay opinion is that schizophrenia is commensurate with hearing voices and paranoia, but this is not true. Hearing voices and paranoia are non-specific phenomena which can occur in normal psychic life.

So what exactly is schizophrenia? Well it is also not commensurate with psychosis. In fact, there is a long list of conditions in which psychosis can occur (Figure 1).

Psychosis we can define as a fundamental shift in a person’s experience of lived reality, affecting the highest faculties of mental life – perception, thinking, beliefs, self-hood.

Causes of schizophrenia

Figure 1: There are numerous causes of psychosis, not just schizophrenia.

Lay opinion also makes the mistake in formulating the psychotic shift as breach from consensual reality, the shared reality of the group. It is not. The psychotic shift is a breach from one’s previous way of being in the world. One aspect of psychosis is key. The sufferer is unaware of the falsity of their new reality, a fact which is obvious to friends and family.

But what is schizophrenia?

Again we return to the question, what is schizophrenia? Here we grasp for an answer. The most important point is that schizophrenia involves a loss. Not just a loss of the previous way of perceiving and thinking about the world, but something deeper. The loss encompasses – human relationships, interests, intellectual pursuits, ambition, motivation, emotional life. At its most extreme, it is the spark of mental life itself which is lost (or markedly impoverished) – the personality, drive, speech, thinking, the will.

In modern psychiatry such phenomena are referred to as the negative syndrome, which obviously denotes loss. The negative syndrome maps onto poorer intellectual abilities, across multiple domains – working memory, episodic memory, processing speed, social cognition – and is associated with functional disability in daily life.(Figure 2).

The domains of schizophrenia

Figure 2: The different domains of schizophrenia.

We can recap. Voices and paranoia are not commensurate with psychosis. Psychosis occurs in a multitude of disorders, not just schizophrenia. Finally, schizophrenia is so disabling because of the loss (or diminution) of all those aspects which make human mental life so special and unique.

Further posts in this series:

What causes schizophrenia?

Future posts in this series:

What happens to the nervous system in schizophrenia?

The prognosis of schizophrenia.

How is schizophrenia treated?

Psychiatric genetics: CNVs are revealing the neuroscience of schizophrenia

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Long stretches of DNA, from 1000 to several million base pairs, can be deleted or duplicated within a chromosome. These changes are known as copy number variants (CNVs). It is now recognised that eight CNVs are associated with schizophrenia. For a person carrying a CNV, their risk of developing schizophrenia is increased by 3-58 times compared to the general population. It is also known that approximately 2.5-5% of people suffering from schizophrenia will carry at least one of these CNVs.

A new paper by Danish researchers serves as an excellent introduction to this rapidly developing and fundamental topic. The authors detail the characteristics of each of the eight CNVs.

The effect of CNVs: Neurexin

The majority of the CNVs harbor multiple genes. The exception is deletion of a stretch of DNA which harbors a single gene coding for a protein called neurexin (NRXN)1.

The molecular biology of glutamate synapses.

Synapses are held together by cell adhesion molecules, one of which is neurexin (NRXN1).
Deletion in the gene for neurexin is a risk factor for schizophrenia and autism.

Neurexin is a component which holds the two sides of a synapse together. When people talk about connectivity in the nervous system, they are talking about components like neurexin. Healthy information processing in the brain depends on healthy stable connections between neurons.

The effect of CNVs: The other seven

Researchers are beginning to understand how the the seven other CNVs might operate to confer risk for schizophrenia, and indeed many other psychiatric syndromes. A property known as pleitropy means that a genetic change actually confers risk for a range of disorders. The CNVs associated with schizophrenia are also risk factors for autism, ADHD, epilepsy and intellectual disability. Indeed, all eight schizophrenia CNVs confer risk for autism spectrum disorders (Table 1).

Copy number variants (CNVs) which confer risk for schizophrenia and other neuropsychiatric syndromes

Copy number variants (CNVs) which confer risk for schizophrenia and other neuropsychiatric syndromes.

Using animal models, researchers can decipher how the CNVs alter brain and behviour since DNA stretches are conserved across mammalian species. Animal models of five of the eight schizophrenia CNVs are now available. Those CNVs have been shown to cause deficits in cognition, social behavior, information processing and synaptic plasticity.

Further developments in this area are bound to reveal much more detail about how altered neuronal dynamics give rise to schizophrenia and other major psychiatric syndromes.

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.

The Treatment of Alcohol Dependence: the utility of genetic testing.

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DNA double helixOne goal in modern medicine is to use genetics to determine the best treatment strategy for an individual patient. A simple, cheap genetic test which predicts response to a particular treatment has clear utility for patients.

To date, psychiatry has lagged behind general medicine, no doubt due to the complexity of CNS tissue and the sheer number of components involved in CNS processing, but the picture is changing. One particular area of interest is the treatment of alcohol dependence.

The pharmacogenomics of topiramate

The drug topiramate started off as an anticonvulsant, but was also been found to be effective in reducing alcohol consumption in heavy drinkers. An American study has advanced our knowledge. Natural variation in the DNA coding for a type of glutamate receptor called the kainite receptor was shown to determine if problem drinkers responded to topiramate treatment.

In those carrying the CC variant at rs2832407, topiramate (200mg/d) markedly reduced the number of heavy drinking days compared to placebo (Fig. 1). Heavy drinking decreased from 5 days per week to approximately 1 day per week in CC subjects treated with topiramate.

topiramate v placebo for heavy drinking by genotype

In a 12 week study, heavy drinkers with the CC genotype at rs2832407 in the kainite receptor showed significant reductions in heavy drinking when treated with topiramate.

 

Definite study

A larger study is now underway, hoping to confirm the initial genetic findings. If the result is replicated, genetic testing may translate to routine clinical practice for heavy drinkers considering topiramate treatment.

This would represent a significant advance in the management of alcohol disorders.

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.