Left-handedness in schizophrenia

..and what it means for the rules of this disorder

Richard Feynman famously compared discovering laws of physics to watching pieces move in a game of chess and trying to interpret the rules. Most of the time, pieces behave in predictable ways, like a bishop moving along a diagonal, while every so often something unexpected happens, like a pawn turning into a bishop when it reaches the end of the board. Finding rules that govern the game have to incorporate all observations of these pieces, including unusual occurrences.

Compared with physics, biological systems are more difficult to predict; they tend to be more complex and less amenable to precise measurement. Psychiatric disorders may be the most difficult biological processes to understand. Features of these disorders are subjective and variable between individuals. Our measurements, for example with neuroimaging, do not necessarily capture the relevant biological processes.

Nevertheless we have a number of well-replicated findings for disorders like schizophrenia. How these observations fit together may uncover the ‘rules’ governing this disorder.

Facts about schizophrenia

In 1998, Richard Wyatt published a summary of ‘facts’ about schizophrenia - observations that had degrees of robustness and seemed inherent to the disorder. Since then, the journal Schizophrenia Research periodically updates these ‘facts’, with the latest appearing in 2011.

Their eight observations with most reproducibility (replicated in multiple studies), durability (standing the test of time), and primacy (inherent feature of the illness) are summarised below:

1. Schizophrenia has an annual incidence of 8–40/100,000/year with relatively similar incidence across continents

2. Schizophrenia is highly heritable and genetic factors consistently contribute to approximately 80% of the variability

3. Total brain volume is reduced, and lateral and third ventricular spaces are larger

4. The disorder is characterised by a mixture of positive (hallucinations, delusions), negative (apathy, amotivation, reduced range of emotion), cognitive (memory impairment), and affective symptoms

5. The severity of different symptoms varies across patients and through the course of the illness

6. Onset of psychotic symptoms is usually during adolescence or early adulthood; age of onset is earlier in males

7. There are significant premorbid impairments (difficulties arising before the onset of the disease) in a substantial proportion of patients

8. Dopamine-2 antagonists (antipsychotics) are the only effective therapeutic agents

I have previously discussed how the Oestrogen Hypothesis may explain differences in the onset of illness in females compared with males. However, it is worth bearing in mind that any overarching theory purporting to explain the rules governing this illness has to take all the above observations into account.

There are additional observations about schizophrenia which are close to ‘facts’ in my book:

• Cannabis, particularly heavy use with high THC content, is a risk factor for schizophrenia (summarised expertly in a Psych Unseen Twitter thread)

• There is a small increased risk of being born in Winter, in the Northern hemisphere

• Complications in pregnancy or birth (such as fetal hypoxia), increase the risk of schizophrenia in the offspring

Another that might be added to the list is a higher proportion of left-handedness in people with schizophrenia. In this post I will examine the evidence for this observation and what it tells us about the rules underlying schizophrenia.

Handedness in schizophrenia

The first meta-analysis of handedness in schizophrenia, led by Iris Sommer and René Kahn, was published in 2001. They grouped left-handed and ambidextrous together as ‘non-right-handed’. The proportion who were not right-handed was 1.5 times higher in people with schizophrenia than the general population. This finding was consistent for studies that assessed handedness in children who were then followed-up to determine whether they developed schizophrenia.

People with schizophrenia were more likely to be non-right-handed compared with patients who had other psychiatric diagnoses - suggesting it is not a generic association with mental illness. A later meta-analysis confirmed there is no association between handedness and depression.

Sommer’s meta-analysis was replicated in 2014, in which it was demonstrated that the association was not an artefact of gender (left-handedness is more common in men) or bias from the questionnaire.

Does left-handedness cause someone to develop schizophrenia? Most readers will know that correlation does not imply causation. Obesity is robustly associated with schizophrenia, but is more likely to be an effect than a cause - i.e. reverse causation due to both antipsychotic medication and sedentary lifestyle.

To understand the connection of left-handedness to schizophrenia, we should first consider what makes someone left-handed.

The causes of handedness

As readers may already know, handedness is determined in the brain. The left cerebral cortex controls the right side of the body and the right cerebral cortex controls the left. The majority of people (~90%) are right handed, with a slightly higher proportion in females than males. Language is usually lateralised to the left hemisphere, although in some left-handed people it can be lateralised to the right hemisphere. Dominance of one side of the body can be observed before birth from fetal movements. Asymmetry in neural development is seen as early as one month following conception.

It was previously thought that a single gene was responsible for right-handedness - the so-called right-shift theory. The gene was never found and it was accepted that handedness is a polygenic trait, controlled by a number of genes, each with small effect.

In 2021, a Genome Wide Association Study (GWAS) examined handedness in 1.8 million people. It found 48 genetic variations associated with handedness. Some of the genes identified are thought to be important for neurodevelopment, while three variants had previously been associated with schizophrenia. Genes aren’t the full story though. The heritability¹ of handedness was estimated by the GWAS at around 12% (for comparison, remember the heritability of schizophrenia is 80%). Clearly, non-genetic factors are also important.

Some early life factors were examined using the UK Biobank. Birthweight, being part of a multiple birth, and being born in Summer were associated with left-handedness. Although various early life factors showed statistically significant association, when combined they had minimal prediction for left-handedness. The authors speculate that, given the majority of individuals are right-handed, perturbations to normal development through environmental or genetic factors could result in left-handedness.

So handedness is likely due to a combination of factors, some genetic, some environmental, and a degree of randomness. This ‘randomness’ or ‘noise’ (known technically as stochastic developmental variation, see this Twitter thread by Kevin Mitchell) is actually an inherent part of neurodevelopment, making each of us unique individuals even if we are genetically identical.

How does this fit with our models of schizophrenia?

It is important to note that the increased proportion of left-handedness in schizophrenia seems to be a robust but small effect. It is just one move of a chess piece that might add something to how we think about the rules underlying this disorder.

In this case, it fits with the neurodevelopmental model, proposed in the 1980s by the likes of Robin Murray and Shôn Lewis. This model proposes that early disturbance to development results in the emergence of psychotic disorders in adolescence or adulthood.

The initial model was based on epidemiological evidence such as birth complications increasing risk, as well as Winter birth (with presumably higher rates of viral infection).

Subsequent research has provided further evidence:

• People with schizophrenia show problems in motor co-ordination that are present from childhood

• Cognitive deficits in schizophrenia can be detected in childhood/adolescence, many years before the onset of the disorder

• MRI scans find higher rates of incidental abnormalities in schizophrenia than healthy controls, suggesting problems in brain development

• A large ENIGMA consortium study showed subtle widespread differences in brain asymmetry in schizophrenia, compared with healthy controls

• There is genetic overlap between schizophrenia and other more classically neurodevelopmental disorders, like autism

• Copy number variants (deletions or duplications in large sections of DNA ) are associated with neurodevelopmental disorders like autism, ADHD, and indeed schizophrenia, but not bipolar disorder

In this regard, the increased proportion of left-handedness might be seen as an epiphenomenon, similar to subtle motor signs or cognitive impairment - consequences of the disrupted development that predisposes to schizophrenia. In keeping with a shared neurodevelopmental cause, autistic people are also more likely to be left-handed than the general population.

Further advances in understanding schizophrenia might come in a similar way - careful observation, replication of findings, and then building models that make sense of the data. In the case of the neurodevelopmental model, unanswered questions remain, chiefly: why does schizophrenia tend to present in early adulthood rather than childhood? We will not have a true understanding of the rules until we have models that make sense of all our observations.

1. Heritability in genetics has a technical definition - the degree of variation in a trait in a population that is due to genetic variation between individuals in that population