16.2: Schizophrenia (SZ)

Schizophrenia is a psychiatric condition affecting just under 1% of people. SZ affects men slightly more often than women and affects people of all races. There is a strong association between low socioeconomic status and the risk of developing schizophrenia, indicating that stresses such as neonatal nutritional deficiency or food insecurity may be risk factors. Other risk factors that contribute to increased SZ risk include prenatal drug exposure, heavy drug use during early adolescence, and childhood adversity.

A diagnosis is generally made while a person is in their late adolescent years through their thirties. During this phase of life, the brain is still undergoing subtle maturation processes, which may account for why a person is more vulnerable in these years. After this age, the risk of developing SZ decreases significantly. Also, the later in life that SZ symptoms appear, the better the health outcomes are.

It is worth noting that people with SZ have the neurotypical range of intelligence, with the occasional outliers: John Nash, the real-life Nobel prize-winning economist depicted in the movie A Beautiful Mind, was first diagnosed with SZ in 1959.

Figure 16.4 Dr. John Forbes Nash was diagnosed with schizophrenia before receiving the Nobel Prize in Economics in 1994.

Symptoms of schizophrenia

The symptoms of SZ can be roughly classified into two categories, positive symptoms and negative symptoms. These phrases are used to describe whether there is an excess of some function (positive symptoms) or a deficit of a function (negative symptoms). The symptoms do not appear uniformly across patients, so not all patients develop every symptom.

The most well-known positive symptom of schizophrenia is hallucinations, perceiving something that is not there (as opposed to illusions, which are misinterpretations of things that are there). Usually, patients experience auditory hallucinations, but they more rarely have visual hallucinations. The voices that these people hear may be consistent or can change over time. Interestingly, the nature of these hallucinations is influenced by society. In cultures with strong ancestor reverence, they may hear the voices of their grandparents, whereas people in religious cultures may hear the voices of deities.

Figure 16.5 Auditory (and sometimes visual) hallucinations are a common positive symptom of SZ.

Relatedly, people with SZ may experience a variety of delusions, untrue beliefs that cannot be changed despite overwhelming evidence. The delusions can come and go spontaneously. Delusions exist in many forms. A paranoid delusion is when a person believes that they are being spied on, maybe by the government or by aliens. A persecutory delusion is a persistent thought that the world is out to get them or to do them harm. Delusions of grandeur are when a person has a tremendously high sense of self-esteem, believing that they are royalty or are the reincarnation of God.

Figure 16.6 Persecutory delusions, a symptom of SZ, is the persistent belief that someone or something is constantly watching you.

Other positive symptoms that can present in SZ are a variety of motor disturbances. Basal ganglia and cerebellar structural deficits are found in SZ, two brain structures involved in motor control (see chapter 10), which may explain why deficits are observed. One motor difficulty is catatonia, where a person can hold their body in a highly unusual position for a prolonged period of time. They may also display stereotypy, a series of repetitive, purposeless behaviors, such as the persistent rocking of the body or self-caressing

The negative symptoms of SZ may include deficits in expression. One common symptom is a flat affect, where a patient does not show or express emotion in situations where you would expect to see them. A related negative symptom is alogia, a decrease in the use of language. People with alogia often use vague language that is lacking in content or repetitive.

Negative symptoms also include deficits in motivation or interest. Two closely-related negative symptoms include anhedonia, a loss of a sensation of pleasure and the inability to expect upcoming pleasure. Furthermore, patients with SZ may also exhibit avolition, a decrease in goal-directed activity, which can cause a person to stop seeing their friends and cease displaying interest in social gatherings, leading to worsened interpersonal relationships.

Figure 16.7 After being moved gently into an unusual body position, a person with catatonia may stay in that position for a prolonged time.

Negative symptoms may also manifest as a deficit of a patient’s cognitive abilities, particularly shortcomings in episodic memory (Chapter 13). They may also present with difficulty in performing attention-related behavioral tasks.

Potential causes of schizophrenia

In a healthy person, dopamine is important for motor control and motivation, two behaviors that are changed in patients with SZ. Therefore, scientists have suggested that abnormal dopamine signaling may be an underlying root cause. While the dopamine hypothesis is one of the earliest theories of SZ, modern genetics studies have shown that polymorphisms in the dopamine D2 receptor are risk factors.

Atypical cortical neuron network development is also likely to be present in SZ. In the healthy brain, networks of cortical neurons produce cyclic patterns of activity in the 40 Hz range, a pattern called a gamma oscillation. These gamma oscillations result from a combination of excitatory and inhibitory neurons. In SZ, there is a decrease in the density of dendritic spines on the excitatory neurons with a simultaneous decrease in GABA-ergic signaling, which leads to unpredictable gamma oscillations.

Figure 16.8 Many environmental factors contribute to the risk of developing SZ.

Animal models of schizophrenia

One animal model for SZ is based on the hypothesis that excess dopamine leads to the disorder. Introducing high doses of the drug amphetamine, which increases dopaminergic signaling, induces a temporary schizophrenic-like state in non-human animals. The hyperdopaminergic model of SZ produces cognitive deficits with no changes in memory or other negative symptoms. Alternatively, administration of NMDA glutamate receptor antagonists, like ketamine or PCP, is also used as a behavioral model of SZ.

Other non-human models of SZ are neurodevelopmental models. In these models, a pregnant dam is exposed to the compound MAM, which causes the newborns to develop atypically and display behavioral deficits similar to SZ. Inducing an unusually strong immune response in the pregnant mother can also cause atypical development in utero, which causes the animals to experience behavioral deficits after birth.

The biggest limiting factor to developing an animal model is that many symptoms in human SZ, like paranoid delusions or auditory hallucinations, are impossible to detect and quantify in nonhumans. The PCP model can cause changes in rodent social behaviors, but it is hard to tell if this model causes any of the positive symptoms that you might see in a patient with SZ. Despite the limitations of these non-human models of SZ, they have been helpful in testing the therapeutic efficacy of anti-schizophrenia drugs.

Treatments of SZ

The dopamine theory of SZ has led to a few novel therapeutic strategies, especially in the context of the dopamine D2 receptor. D2 antagonists decrease hallucinations and delusions in some patients with SZ, and the effectiveness of the antagonist is correlated with the ability of that drug to block the D2 receptor. Clozapine, an atypical antipsychotic that functions as a dopamine receptor antagonist, can decrease SZ symptoms as well.

Unfortunately, pharmacological therapies are not always effective in humans. Around a third of patients discontinue their treatment regimen, and around a fifth of them report adverse side effects such as extrapyramidal motor symptoms, sedation, and weight gain.

A potential new therapy is based on transcranial magnetic stimulation (Chapter 6). Some evidence suggests that targeted activation of the cortex can decrease the severity of auditory hallucinations. There may also be some mild improvements in the negative symptoms.

Approximately 65% of North Americans with SZ are smokers, compared to 25% in the population at large. If they are smoking as self-medication to activate dopamine- or acetylcholine-sensitive networks in the brain, this observation may lead to a new therapeutic strategy. Alternatively, they may smoke to get pleasure, which acts to reverse the anhedonia

Figure 16.9 Atypical dopamine signaling is believed to contribute to schizophrenia.