April 29, 2024	PSY 340 Brain and Behavior Class 40: Psychological Disorders: Schizophrenia

Schizophrenia (SCZ)

What are the mental disorders which lead to the greatest rate of inpatient hospitalization in the United States?
Here are data showing the rate for the 5 leading causes:



(1) Depressive disorders,
(2) Schizophrenia spectrum & other psychotic disorders,
(3) Bipolar & related disorders,
(4) Suicidal ideation or attempt & intentional self-harm, and
(5) Trauma- & stressor-related disorders (e.g. PTSD)

In this class we will look at #2 Schizophrenia and in the next two classes #1 Depressive & #3 Bipolar disorders

NOTE: The DSM-5 (2013) and DSM-5-TR (2022, the latest revision) use a larger category called Schizophrenia Spectrum and Other Psychotic Disorders within which SCZ is one type of disorder. The elements common to "psychotic disorders" (and described below) include (1) hallucinations, (2) delusions, (3) disorganized thinking (speech), (4) grossly disorganized or abnormal motor behavior (including catatonia), and (5) negative symptoms

YouTube Video: Interview of Young Female at Northwestern Medicine (3'03")
Diagnosis

Schizophrenia (often abbreviated as SCZ) was originally called dementia praecox (= "mental deterioration or madness coming early in age"). Swiss psychiatrist, Eugen Bleuler (1857-1939), came up with the term schizophrenia (= "split mind") in 1908, which has been preferred ever since (Ashok et al., 2012). The split is between the thinking and emotional processes (NOT between different personalities which is Dissociative Identity Disorder [formerly called "Multiple Personality Disorder"])

Schizophrenia (DSM-5) in general is diagnosed by the presence of at least a couple of these key features:

 A.  "Positive Symptoms" (i.e., excesses or behaviors that shouldn't be there but are)

• Delusions (beliefs that are false, e.g., persecution ["The government is listening to my thoughts"], grandiosity ["I am Jesus Christ"], etc.)
• Hallucinations (false sensory experiences, e.g., auditory (hearing voices that aren't there) or visual (seeing things that aren't there))
• Disorganized Thinking & Speech (incoherence, illogical speech)
• Grossly Disorganized or Abnormal Motor Behavior (agitation, aimless activities, etc.)
  

• Diminished or inappropriate emotional expression (e.g., failure to respond in emotionally appropriate ways or flatness in the expression of any feelings).
  
• Avolition = inability or difficulty in initiating or engaging in goal-directed behavior),  i.e., a significant decrease in self-initiated, motivated behaviors or socializing with others.
  

C.  Cognitive Impairments

• While these symptoms are not directly used to diagnose SCZ, most individuals with SCZ have significant problems involving their cognitive functioning, especially verbal & visuospatial memory, attention, executive function, and speed of processing (Hurford et al. 2011). Clinical researchers are increasingly focusing upon cognitive impairments in understanding SCZ.

• In a 30-year longitudinal study among 1,037 boys and girls born in New Zealand during 1972-1973, impaired levels of cognitive functioning were seen in young children and adolescents (7-13 years old; N = 35 or 3.5% of the sample) before they developed or were diagnosed SCZ (Reichenberg et al., 2010). Children who were diagnosed with SCZ as adults showed [1] "developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. [2] In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory" (Abstract). See data above on the left.
  

• Using standard neuropsychological tests, Bilder et al. (2000) compared patients with first-episode schizophrenia who had stabilized on medication with a sex/age matched comparison group of adults without any psychiatric disorder. They found very large overall cognitive deficits (averaging 1.5 standard deviations lower than the controls) with other more subtle deficits involving memory & executive functions. See data above on right.
  

Schizophrenia can be either acute (a sudden onset with a good possibility of returning to normal in a short time) or chronic (a gradual onset and a long-term course).

Prognosis (= the future outcome) for SCZ is generally much poorer than for any other mental disorder other than the dementias

• In one study of patients followed over 26 years, only 46% of SCZ patients compared to 80% of patients with a mood disorder had 1 or more years without symptoms of their disorder (Jobe & Harrow, 2010)

• About 25-35% of SCZ patients tend to show a chronic or continuous experience of psychotic symptoms while only about 10-15% recover quickly and completely without any further symptoms. The remainder show periods of SCZ with relative recovery and, then, relapses.


• Multiple studies of long-term outcome suggest that symptoms tend to stabilize after 5 years and do not worsen after that (Jobe & Harrow, 2010)

• Patients with SCZ using cannabis have a poorer prognosis than those who do not.

• Suicide: About 5-6% of individuals with SCZ die by suicide and about 20% attempt suicide at some point (often with continuing suicidal thoughts; APA, 2022)
  

• Although there is some disagreement on this finding, patients in the developing world (e.g., in Africa or Asia) tend to have better outcomes than patients in the developed world (e.g., in the US or Europe)

• Early death: Researchers have noted for years that persons with a diagnosis of SCZ die on average 20 years earlier than age-matched control subjects (Laursen et al., 2014; Miller, 2023). Why? In addition to the rate of suicide, other factors include: (1) Adverse effects of medications; (2) poor lifestyle; (3) other bodily comorbidities; (4) poorer treatment of other body disorders; and (5) accelerated ageing/genetic factors (Laursen, 2019).

Demographic Data (McGrath et al., 2004, 2008; Saha et al., 2005)

a. Ethnicity: Schizophrenia occurs in all ethnic groups

b. Gender

• SCZ is somewhat more prevalent in men than women (7:5 ratio).
• SCZ may develop anytime between the late teens and the early 30s.
• The peak age for development in men comes at an earlier age (early to mid-20s) than in women (late 20s) and is more serious.

c. Urbanicity: SCZ is more prevalent in urban areas vs. rural areas across the world

d. Migrant Status: SCZ is more prevalent in migrants than native-born adults (4.6:1 ratio)

e. Economic Development: SCZ is somewhat more prevalent in US/Europe than in developing countries ("Third World").

• World-wide adult prevalence in any one year used to be estimated at almost 1%. As our text argues, recent data show this is almost certainly an overestimate and we should probably now use the figure of 0.5%.

• The lifetime prevalence is moving downward from the traditional estimate of 1% to 0.7 even lower (e.g., Jeffries et al., 1997;  Woogh, 2001). Indeed the DSM-5 and DSM-5-TR claim a lifetime prevalence of 0.3 to 0.7%. Similarly, the World Health Organization (WHO, 2022) claims that SCZ "affects approximately ... 1 in 300 people (0.32%) worldwide." We now think that, at most, 7 or 8 people in every 1,000 will develop SCZ in their lifetime.

A. Genetics: High Heritability

1. Twin and Family Studies. For monozygotic schizophrenic twins there is about a 50 percent concordance (agreement), and a 17% concordance for dizygotic twins. The greater concordance in monozygotic twins does not necessarily mean a genetic cause, as a pure genetic effect would have a 100% concordance.

The greater environmental similarity in monozygotic twins, as compared to dizyogotic twins, may also influence concordance rates. Note that dizygotic twins are actually siblings and their concordance rate for SCZ is more than twice that of siblings born at other times. Dizygotic twins share the same prenatal environment.

In family studies, concordance rates for SCZ go up the closer individuals are genetically related to someone with SCZ.

2. Adopted Children. Adopted children who develop schizophrenia usually have adopting relatives that are psychologically normal, but a high percentage of the biological relatives have schizophrenia.

3. The overall heritability of SCZ across multiple studies appears to be roughly around 80%, considerably higher than found for major depressive disorder, but in line with bipolar disorder (Hilker et al. 2018).

Prelude to B.

The following studies look at single nucleotide polymorphisms (SNPs) in the DNA of research participants. As Wikipedia explains: "A Single Nucleotide Polymorphism (SNP, pronounced snip; plural snips) is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes. For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide [highlighted in boldface & red]. In this case we say that there are two alleles. Almost all common SNPs have only two alleles." See the illustration to the right.

B. Genome-Wide Association Studies (GWAS)

• SCZ Is Linked to Many Genetic Variations. In 2014, the Schizophrenia Working Group of the Psychiatric Genomics Consortium reported on differences found in the complete genomes (all the different genes in the DNA of each person) collected from over 150,000 people (~37,000 people w/SCZ & ~113,000 people without SCZ/"healthy controls")
• They identified 128 individual genetic variants (SNPs) at 108 specific places (called "loci") among the chromosomes of those with SCZ. 83 of these loci had not previously been reported.
  
• Each of these genetic variants seems to contribute a small share of the risk of developing SCZ
• The more of these variants persons have = the more likely they are to develop SCZ
• This study put an end to the notion that there is anything like a single or small number of SCZ genes.

• More recently Pardiñas et al. (2018) reported a total of 145 SNPs related to SCZ in an analysis of the genomes of 11,260 SCZ patients and 24,542 controls (more than half of whom had never previously been analyzed in earlier studies). Further, they found across the genome six sets of genetic alleles (ranging in size from 16 to 1,939 alleles per set), each of which are "independently associated with SCZ and point to molecular, physiological and behavioral pathways involved in SCZ pathogenesis [development]) (p. 6).
  

 

• Challenging SCZ as a Single Disorder. In the American Journal of Psychiatry Arnedo et al., (2014) reported a new set of GWAS studies undertaken at Washington University School of Medicine in St. Louis, MO. They found 42 pairs of SNPs (single nucleotide polymorphisms). each of which was associated with a 70% to 100% risk of SCZ. And, a total of 98 SNP pairs accounted for 90% of the cases in their study (4,196 persons with SZ and 3,827 controls without SCZ). The replicated their findings with an 81% success rate among patients with SCZ in two other separate groups of patients.
  

• "[Arnedo et al, 2014] then divided patients according to the type and severity of their symptoms, such as different types of hallucinations or delusions, and other symptoms, such as lack of initiative, problems organizing thoughts or a lack of connection between emotions and thoughts. The results indicated that those symptom profiles describe eight (8) qualitatively distinct disorders based on underlying genetic conditions" (Dryden, 2014). The distinctive disorders are described (Table 3) as

• Severe process with positive and negative symptom SCZ
• Positive and negative SCZ
• Negative SCZ
• Positive SCZ
• Severe process, positive SCZ
• Moderate process, disorganized negative SCZ
• Moderate process, positive & negative SCZ
• Moderate process, continuous positive SCZ

• The DSM-5-TR (APA, 2022) summarizes the genetic/hereditary data in this way: "“There is a strong contribution for genetic factors in determining risk for schizophrenia, although most individuals who have been diagnosed with schizophrenia have no family history of psychosis. Liability is conferred by a spectrum of risk alleles, common and rare, with each allele contributing only a small fraction to the total population variance. The risk alleles identified to date are also associated with other mental disorders, including bipolar disorder, depression, and autism spectrum disorder” (p. 118, emphasis added)

• Note that, despite finding genetic markers which are highly implicated in the development of SCZ, the direct cause of the disorder, that is, why it emerges, almost certainly involves an interaction with environmental and other factors.
  

C. The Neurodevelopmental Hypothesis: Schizophrenia is caused in large part by abnormalities to the nervous system during the prenatal or neonatal periods.

1. Prenatal and Neonatal Environment

a. Father over age 55 & living in a city rather than suburb/rural areas (intermediate risk factors)

a. Many people with schizophrenia had problems before or shortly after birth that could have affected their brain development, including poor nutrition and low birth weight, and complications during delivery such as extensive maternal bleeding or prolonged labor. (small risk factor)

b. Schizophrenia has been linked to problems in early or middle pregnancy. During WWII, Dutch women who were on a starvation diet in the early stages of pregnancy gave birth to a high percentage of babies who later developed schizophrenia. (small risk factor)

c. Rh incompatibility between mom and offspring is associated with increased probability of schizophrenia, especially in boys and later-born babies. (small risk factor)

d. Season-of-birth effect: Tendency for those born in winter to have a slightly greater probability of developing schizophrenia; this tendency occurs only in nontropical climates. Many scientists believe that a viral infection during a fall pregnancy accounts for the season-of-birth effect. (small risk factor)

2. Mild Brain Abnormalities

a. Early MRI studies reveal that many schizophrenics have a slightly smaller prefrontal cortex, temporal cortex, hippocampus, and amygdala than non-schizophrenic adults. They also have larger than normal ventricles.

b. The areas of the brain that most consistently show signs of abnormality in schizophrenics are the ones that mature the most slowly, such as the prefrontal cortex.

c. At a microscopic level people with schizophrenia have smaller than normal cell bodies and some of their neurons fail to arrange themselves in the neat orderly manner of normal brains.

d. People suffering from schizophrenia have slightly larger right hemispheres; while non-schizophrenic adults tend to have larger left hemispheres. Schizophrenics also have lower than normal overall activity in the left hemisphere.

e. Lowered connections between cortical areas. More recent DTI (diffusion tensor imaging) has documented significant white matter tract abnormalities in the connections between different areas of the brain for patients with SCZ (Romme et al, 2016). These reductions in network connectivity are particularly noticeable in the frontal, striatal (subcortical areas of the basal ganglia), and thalamic regions (Bohlken et al, 2015).

• Note that both of these studies of white matter tract abnormalities found these differences while studying multiple genetic SNPs which were previously associated with SCZ. These researchers note that many of these genes are involved in some way in actually building different aspects of the nervous system and, thus, it should not be surprising that such genetic variations might, AS A WHOLE, contribute toward abnormal white matter connections.

f. University of Pennsylvania researchers recently reported two subtypes of SCZ related to whether or not there were abnormalities in brain size and structure. “Subtype 1 showed a commonly reported pattern of widespread reduced grey matter relative to healthy controls [~63% of their sample] … whereas Subtype 2 demonstrated increased volume of the basal ganglia and internal capsule against a background of normal grey and white matter [~37% of their sample]… Our findings thus challenge dominant views of widespread brain volume reduction in schizophrenia” (Chand et al., 2020, p. 7). Notably, neither patient groups differed in terms of symptom severity, duration of illness, age at onset or medication dose or type of medication.

3. Early Development & Later Psychopathology = Why are Symptoms Delayed until Adolescence? An important issue related to the neurodevelopmental hypothesis is

Why do the symptoms show up after in late adolescence or early adulthood if the damage occurs early in brain development?

The answer to this is not clear although as the Neuro-Inflammatory Hypothesis (described below) suggests whatever damage occurs during gestation and early childhood is followed by continued damage to the neural connections in the CNS in adolescence and beyond.

• Recent research in the UK shows a definite presence of "psychotic"-like symptoms (hallucinations, delusions) among children as young as 12 years old (Polanczyk et al, 2010). Earlier longitudinal research with 11-year-old children in New Zealand found that about half those who reported psychotic-like symptoms as children developed SCZ as adults (Poulton, Caspi et al, 2000). Later research suggests that the 50% risk is too high & that it is rather between about 16 and 35% of young high-risk children who eventually develop full-blown SCZ (Morgan et al., 2020).
  

• Building upon these findings, even more recent research has identified a pattern of proteins in blood samples of high-risk children in the New Zealand study at age 12 that was predictive of their development of SCZ by late adolescence/early adulthood with 93% accuracy (Morgan et al., 2020).
  

D. The Neuro-Inflammatory Hypothesis: Overactive Immune System (Johnson & Stevens, 2018)

As Clifton et al (2019) point out, "the transition from late childhood into adolescence represents a profound period of frontal cortical maturation. In particular, this period is characterized by the elimination ("pruning") of excitatory synapses in the frontal cortex resulting in changes in excitatory-inhibitory balance and dopaminergic regulation and the emergence of adult patterns of executive functioning" (p. 74).  As young children move through later childhood into adolescence, the density of synapses in the cortex decreases. In the figure on the left, Huttenlocher & Dabholkar (1997) show the decreasing density of synapses from childhood through adolescence in the prefrontal cortex (dark brown), visual cortex (blue), and auditory cortex (red).

In 1983 Irwin Feinberg speculated that the reason why the symptoms of SCZ only emerged in adolescence or the early 20s was due to damage to the ordinary processes of synaptic pruning in the adolescent brain. He suggested that there was either too much or too little pruning and that impaired process was directly related to the emergence of SCZ symptoms (Johnson & Stevens, 2018). This is the background to the "Neuro-Inflammatory Hypothesis" of SCZ.

According to the "Neuro-Inflammatory Hypothesis," something goes wrong in the ordinary loss of synapses because of some type of inflammatory or infectious process. Thus, schizophrenia is caused at least in part by a reaction of the brain's immune system (the microglia) which is hyperactive up to and including the adolescent period. As a result the microglia prune (= eliminate) too many synaptic connections, particularly in the prefrontal region of the brain. Note that (1) the inflammatory process in adolescence may be in addition to other genetic vulnerabilities which are expressed before adolescence and (2) inflammatory processes may also be at the root of other mental disorders including major depression (e.g., Bullmore, 2018).

As Costandi (2019) summarizes, the lines of evidence for this hypothesis include

• Changes in the brain's structure and function in schizophrenia gets worse over time. "Psychosis is associated with reduced grey matter volume in the frontal, temporal, and parietal lobes while auditory hallucinations are associated with altered functional connectivity between the frontal and temporal lobes."
  

• Bloomfield et al. (2016) compared patients with SCZ, high risk patients for psychosis, and normal controls in a PET scan study and found that microglia were far more active in the brains of SCZ and high-risk patients compared to controls. This implicated a neuro-inflammatory process in psychosis. 
  

• Individuals who have schizophrenia or are at high risk to develop SCZ show elevated levels of cytokines in their blood plasma. Cytokines [such as interleukin (IL)-1β, IL-2, IL-6, and interferon (IFN)-γ] are a class of molecules in the immune system which fight infections and are associated with proinflammatory processes. In the brain cytokines activate microglia cells. A survey of the research by Rodrigues-Amorim and colleagues (2018) "confirm[ed] the existence of cytokine abnormalities in schizophrenia disease ... [and] provide strong evidence of a concommitant process of inflammatory activity in schizophrenia illness course" (Abstract).
  

• In studies of developing rats, Mallya et al. (2018) were able to establish that microglial cells do prune dendritic spines of the cortex during the period of rat development equivalent to human adolescence. It is notable that clear symptoms of SCZ in humans appear in adolescence rather than earlier (though there are signs of some abnormal functioning in children who later develop SCZ). 
  

E. Neurotransmitter Hypothesis and Drugs

1. Dopamine hypothesis for schizophrenia = schizophrenia results from excess activity at certain dopamine synapses. The "dopamine hypothesis" for schizophrenia was first proposed by Solomon Snyder (1976). The primary evidence for this hypothesis is the type of drugs that relieve and aggravate the symptoms of schizophrenia. a. Chlorpromazine (Thorazine): First drug used successfully for the treatment of schizophrenia. First sold in 1955. b. Antipsychotic drugs: Drugs used for the treatment of schizophrenia. These drugs work primarily by blocking dopamine receptors. Phenothiazines includes chlorpromazine (Thorazine). Butyrophenones includes haloperidol (Haldol). c. Substance-induced psychotic disorder: Disorder characterized by hallucinations and delusions caused by drugs such as cocaine, amphetamine, and LSD that increase the activity of dopamine synapses. d. Stress exacerbates the symptoms of schizophrenia and causes the release of dopamine from the prefrontal cortex, an area believed to be important in schizophrenia. e. Excess production and release of dopamine cannot be the sole cause of schizophrenia. Drugs that block dopamine receptors do so almost immediately, but their effects on behavior build up gradually over 2 or 3 weeks.    Levels of dopamine and its metabolites are generally normal in schizophrenics. f. Recent studies indicate that schizophrenic people have about twice as many D2 receptors occupied by dopamine as normal people.

2. Glutamate hypothesis for schizophrenia = schizophrenia results from deficient activity at certain glutamate synapses, specifically involving NMDA receptors Because dopamine inhibits glutamate activity in many parts of the brain, much of the evidence supporting the dopamine hypothesis of schizophrenia also supports the glutamate hypothesis of schizophrenia. This hypothesis emerged in the 1990s and has gotten a lot of research activity in the last 20 years (Javitt, 2014) a. Researchers have found that the brains of schizophrenic people release lower than normal amounts of glutamate in the prefrontal cortex and hippocampus. Schizophrenics also have fewer glutamate receptors. b. Phencyclidine (PCP or "Angel Dust") and Ketamine ("Special K"). These drugs block glutamate-type NMDA receptors and used as an anesthetic in veterinary surgery (Ketamine in human surgery as well). These drugs administered to "normal people" produces a type of psychosis more similar to schizophrenia than drugs like cocaine since both induce negative as well as positive symptoms.    PCP does not produce psychosis in preadolescents but produces a much more severe psychosis in people with a history of schizophrenia. c. Because increasing glutamate activity in the brain would be extremely risky (glutamate is used all over the brain in many different regions), there are no drugs used to treat schizophrenia which directly stimulate glutamate activity. However, there are some experimental compounds that may someday be used to treat schizophrenia. As of the early 2020s, there are still no approved treatments coming out of this hypothesis.

3. The Search for Improved Drug Treatment

a. Mesocorticolimbic system: There are four dopamine pathways in the brain of which two are important for biological psychology.

• The mesolimbocortical system has two parts: (1) the mesocortical pathway which projects into the prefrontal cortex and is involved in executive decisionmaking and (2) the mesolimbic pathway which projects into the striatum in the limbic system (including the nucleus accumbens) and is involved in reward-related cognition (e.g., reinforcement, pleasure, salience). The mesocorticolimbic system is believed to be the area in which antipsychotics have their beneficial effects.
  

• The nigrostriatal system which uses dopamine is involved with Parkinson's disease, not SCZ.

b. Tardive dyskinesia (Caroff et al., 2011).  A serious side effect of first-generation or older antipsychotics from the 1950s & 1960s; this disorder is characterized by tremors and other involuntary movements. It arises in 20%-30% of patients on long-term antipsychotic medications, more frequently among patients over the age of 45. It often begins insidiously, that is, with small involuntary movements which get worse over time. It is generally incurable, but clinicians will usually discontinue treatment when the symptoms are still mild. Tardive dyskinesia is probably due to denervation supersensitivity caused by the prolonged blockade of dopamine receptors.

c. Atypical antipsychotics: Newer drugs (e.g., clozapine) that alleviate the symptoms of schizophrenia while seldom, if ever, producing movement problems such as tardive dyskinesia. These drugs have less intense effects on dopamine type D2 receptors, but stronger effects at D4 and serotonin 5-HT2 receptors

d. Atypical antipsychotics alleviate both positive and negative symptoms of schizophrenia. Unfortunately, these compounds have their own side effects, including increased risk of diabetes and an impairment of the immune system.

Where are we today?

Despite all of these advances in understanding possible causes or factors associated with the development of SCZ, the solution to understanding the nature, origins, and treatment of this terrible disorder is still not clear. As science has developed more and more powerful tools to investigate the living brain and as we gain greater knowledge of both the biological and environmental worlds in which people live, we uncover even more questions. For example, the use of DTI (diffusion tensor imaging) is only about 12 years old and we had no real idea about difficulties in white matter connectivity before the advent of DTI in the brains of SCZ patients. Similarly, the use of GWAS in the last five years has revealed how many more genetic variants there are associated with SCZ than we had known beforehand.

It is fair to say, however, that schizophrenia is almost certainly not a single disorder, but a family of different disorders which are given a single diagnostic label.

So, it would seem, that we have many more years to go before we will have gotten a nearly complete handle on this disorder.

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References

The first version of this page was posted on May 5, 2005