April 26, 2025	PSY 340 Brain and Behavior Class 40: Psychological Disorders: Schizophrenia [Outline]

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

Schizophrenia (SCZ)

NOTE: The DSM-5 (2013) and DSM-5-TR (2022, the latest revision) use a larger category of 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 & usually abbreviated as SCZ) was originally called dementia praecox (= "mental deterioration or madness coming early in age"). Swiss psychiatrist, Eugen Bleuler, came up with the term schizophrenia (= "split mind") in 1908, which has been preferred ever since. The split is between the thinking and emotional processes (NOT between different personalities which is Dissociative Identity Disorder (formerly, Multiple Personality Disorder))

Schizophrenia (DSM-5)

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

• Delusions
  
• Hallucinations
  
• Disorganized Thinking & Speech
  
• Grossly Disorganized or Abnormal Motor Behavior
  

• Diminished or inappropriate emotional expression
  
• Avolition (inability or difficulty in initiating or engaging in goal-directed behavior)
  

Cognitive Impairments

• intellectual deficits apparent in childhood and continue into adulthood
  
• verbal & visuospatial memory, attention, executive function, and speed of processing

Schizophrenia can be either acute or chronic

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

• 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.
  

• 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).
  
  
• Early death: Individuals with a diagnosis of SCZ die on average 20 years early than age-matched controls without SCZ. 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.
  

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

a. Ethnicity: in all ethnic groups
b. Gender: 7:5 ratio M:F
c. Urbanicity: higher in urban than rural areas
d. Migrant Status: 4.6:1 ratio migrant:native-born adults
e. Economic Development: somewhat more prevalent in rich vs. poor countries

• World-wide adult prevalence = about 0.5% (old estimate: 1%)

• The lifetime prevalence is moving downward from the traditional estimate of 1% to 0.7 even lower. Indeed the DSM-5 claims a lifetime prevalence of 0.3 to 0.7%.
  

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A. Genetics: High Heritability

1. Twin and Family Studies.
2. Adopted Children
3. Estimated heritability ~ 80% (significantly higher than major depressive disorder but similar to bipolar disorder)

B. Genome-Wide Association Studies (GWAS)

• SCZ Is Linked to Many Genetic Variations
• 128 genetic variants at 108 specific places (loci). Each contributes a small risk (Schizophrenia Working Group, 2014)
• 145 SNPs and 6 sets of alleles independently related to SCZ (Pardiñas et al., 2018)

• Challenging SCZ as a Single Disorder: Eight (8) qualitatively distinct disorders [Arnedo et al., 2014] = consistent with "Schizophrenia Spectrum Disorder"
  

• 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

While there is a strong contribution for genetic factors, most individuals who have been diagnosed with SCZ have no family history of psychosis (DSM-5-TR, p. 118)

C. Neurodevelopmental Hypothesis: SCZ is caused by damage to the CNS during the Prenatal & 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. 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. (small risk factor)

c. Rh incompatibility between mom and offspring. (small risk factor)

d. Season-of-birth effect  (small risk factor)

2. Mild Brain Abnormalities

• Slightly smaller prefrontal cortex, temporal cortex, hippocampus, and amygdala and larger than normal ventricles.
• Smaller than normal cell bodies and some of their neurons fail to arrange themselves in the neat orderly manner of normal brains.
• Slightly larger right hemispheres and lower than normal overall activity in the left hemisphere.
• Lowered connections between cortical areas, white matter tract abnormalities, and reductions in network connectivity.
• New research (2020) challenges claim of overall brain size/volume abnormalities and finds these differences in about 2/3rd of SCZ patients, not all of them.
  

3. Early Development & Later Psychopathology = Why Are Symptoms Delayed until Adolescence?

Why do the symptoms show up after 20 years of age if the damage occurs early in brain development?

• Some findings of psychotic-like symptoms in children as young as 11 or 12

• See Neuro-Inflammatory Hypothesis below

D. Neuro-Inflammatory Hypothesis: Overactive Immune System

• Ordinary development includes significant elimination ("pruning") of synaptic connections in brain in late childhood & adolescence
• Hypothesis: In SCZ, some process (perhaps a long-term infection. etc) causes the brain's immune system (i.e., microglial cells) to prune too many synaptic connections, particularly in the prefrontal cortex.
  
• Evidence:
•  Structure and functional brain changes get worse over time in SCZ
•  Patients with SCZ or at high risk of developing SCZ show elevated levels of pro-inflammatory cytokines which fight infections and stimulate microglial cells
• Among rats reaching the adolescent stage of maturity, microglial cells have been shown to prune dendritic spines (i.e., synapses)
  

E. Neurotransmitters and Drugs

1. Dopamine hypothesis for schizophrenia = schizophrenia results from excess activity at certain dopamine synapses. a. Chlorpromazine (Thorazine) b. Antipsychotic drugs Phenothiazines includes chlorpromazine (Thorazine). Butyrophenones includes haloperidol (Haldol). c. Substance-induced psychotic disorder d. Stress exacerbates the symptoms of 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 NMDA receptors. a. Lower than normal amounts of glutamate b. Phencyclidine (PCP or "Angel Dust") and Ketamine ("Special K") 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. no drugs used to treat schizophrenia which directly stimulate glutamate activity.

3. Muscarinic hypothesis for schizophrenia The muscarinic hypothesis of schizophrenia postulates that the muscarinic ACh [acetylcholine] system plays a crucial role in the pathology and treatment of schizophrenia. Data from clinical, postmortem, neuroimaging, and preclinical and clinical pharmacology studies support this hypothesis. In the central nervous system, the cholinergic system has extensive branches in the spinal cord, thalamus, limbic system, and cortex. Acetylcholine receptors subdivide into two types: nicotinic - ion channels for sodium and calcium, and muscarinic -coupled with G proteins. The muscarinic hypothesis of schizophrenia suggests that dysfunction in cholinergic pathways may contribute to psychosis, cognitive impairments, and emotional dysregulation. The muscarinic cholinergic system, specifically the M1 and M4 receptor subtypes, offers a promising alternative target in schizophrenia treatment. New medications are in development to target the muscarinic receptors and they have shown promise of helping. These include Xanomeline: One of the most promising agents in this new class of treatments is xanomeline, an FDA-approved selective M1/M4 muscarinic receptor agonist. Clinical trials revealed that xanomeline could reduce both positive and negative symptoms—without the weight gain, sedation, or motor adverse effects that plague dopamine blockers.

3. The Search for Improved Drug Treatment

a. Mesocorticolimbic system

• one of four brain networks using dopamine (DA) & the target for antipsychotic medications
• mesocortical pathway = executive decision making (profrontal cortex)
• mesolimbic pathway = reward-related cognition
  

b. Tardive dyskinesia

c. Atypical antipsychotics: New drugs (e.g., clozapine) that alleviate the symptoms of schizophrenia while seldom, if ever, producing movement problems.

d. Increased risk of diabetes and an impairment of the immune system with atypical antipsychotics.

Where are we today?

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