Monthly Archives: September 2018

Understanding Schizophrenia 2: What causes schizophrenia?

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The Royal Bethlem psychiatric hospitalThe previous post in this series described the symptoms of schizophrenia. Here we turn to the causes of schizophrenia. There has been major progress in this area over the last twenty years. A number of factors have been identified which carry a risk for schizophrenia. Some of these factors are genetic, others impact during the course of life.

Usually schizophrenia emerges in late adolescence or early adulthood, as the intellect, personality and neural networks are being sculpted. The population risk is slightly less than 1%, with a slight excess of male sufferers (1.4:1). Males also tend to show a more severe pattern of illness, with more impoverishment of the personality and psychological decline.

Risk Factor Categories

The risk factors for schizophrenia can be grouped into several categories (Figure 1). The perinatal category includes hypoxic and nutritional insults to the developing brain in-utero. The second category includes being brought up in city environment, particularly for immigrants. The third category includes drugs of abuse, specifically strong cannabinoid CB1 receptor agonists. Finally, there is the genetic category, which can be subdivided into single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).

Figure 1. Risk factors for schizophrenia.

Figure 1. Risk factors for schizophrenia.

Genetic risk factors

It has long been recognized that schizophrenia runs in families (Figure 2), but until the last decade attempts to identify specific genes floundered. Technological advances have revolutionized the field. It is now feasible to screen an individual’s DNA at every base pair (A, T, C, G) in every chromosome. Variants (say the substitution of an A for a T) are called single nucleotide polymorphisms (SNPs) when they occur in at least 5% of the overall population.

In the technique known as GWAS (genome wide association study) tens of thousands of patients are compared against tens of thousands of controls. So far, 145 SNPs have been shown to confer risk for schizophrenia (Figure 3). Each SNP on its own carries a very small risk, but they are common in the population, and their effects are additive. Two SNPs of considerable interest are the gene for a calcium channel (CaV1.2) and the gene for a protein called complement C4a.

Figure 3. Single nucleotide polymorphisms which confer a risk for schizophrenia.

Figure 3. Single nucleotide polymorphisms which confer a risk for schizophrenia.

The second major breakthrough in schizophrenia genetics are copy number variants (CNVs). Copy number variants are deletions or duplications of a long stretch of DNA, typically incorporating half a dozen genes or so. So far eight CNVs which confer a risk for schizophrenia have been identified. Each of these CNVs carry a very high risk. A CNV of considerable interest is NRXN1 (Figure 4).The NRXN1 protein forms a physical bridge which stabilses synaptic connections in the brain. The NRXN1 story provides strong evidence for a long-held theory that the pathology of schizophrenia stems from abnormal connectivity within neural networks.

Figure 4. Copy number variants associated with schizophrenia.

Figure 4. Copy number variants which carry a risk for schizophrenia.

We can recap. A number of factors confer risk for the development of schizophrenia. These can be categorized into several categories – perinatal, environmental, cannabinoid CB1 drugs, and genes. The gene category includes SNPs (such as, complement C4a, the calcium channel CaV1.2) and CNVs (such as NRXN1). In the next post in this series we will look at the neurobiology of these components and cannabinoid CB1 drugs.

Further posts in this series:

What exactly is schizophrenia?

 Future posts in this series:

What happens to the nervous system in schizophrenia?

The prognosis of schizophrenia.

How is schizophrenia treated?

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.