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Schizophrenia, History: Kraeplin

SZ consists of a large range of symptoms
o Conceptualized as one disorder, but it is most likely multiple disorders

Emil Kraepelin, 1904
• A student of Wundt’s experimental lab
• Later became the chief psychiatrist in Estonia
• Father of modern European psychiatry

Created an illness classification system
• Which was the first since Hippocrates
• Both believed illness was due to bodily imbalance

First used the term “dementia praecox” to label SZ
• Translated meant an early onset of deteriorating mental functioning
• Used term to distinguish SZ from bipolar – which was previously grouped


Schizophrenia, History: Bleuler

Eugen Bleuler, 1911

Noticed dementia praecox occurred at different ages, and some people recovered

Guided by a desire to be like Freud and his tendency to use metaphors

Believed the underlying problem stemmed from “loose associations”
o Which led to a “split mind”
• Hence the name “schizophrenia”

Failed to properly operationalize “loose associations”
o Led to an abstract construct of the disorder in the US

The US followed Bleuler's definition, while Europe continued to rely on Kraepelin’s more specific definition

**U.S. thus experienced a surge in hospitalizations due to SZ over-diagnosis, and increase in lobotomies


Schizophrenia as "Salience Disorder"

Current trend is a push to relabel schizophrenia as “salience disorder”

Salient = ability to focus on appropriate stimuli

Hallucination may reflect the inability to recognize the subjective value of experiences from an internal representation/source


Schizophrenia: Onset and Prevalence

In DSM-III, age 34 was the cut off for being able to obtain a diagnosis of SZ

Current DSM does not have a cut off age (but geriatric onset is very rare)

SZ typically develops around puberty

Lifetime prevalence ~ 1%

Some evidence of gender differences
o Men typically demonstrate more severe cases
o It has been argued estrogen serves as a protective factor


Risk factors: Age of Father

Possibly due to degeneration of sperm

Similar link with autism

Potentially encourages social deficits

No specific cutoff age, but 40+ is considered at risk
(Similar to mothers 40+ and link to Down Syndrome)


Risk Factors: Immigration status; Marriage

Affects more immigrants, but cause vs effect?
o Could be more people with SZ flee their native countries due to persecution

• Common for men with antisocial personality disorder to marry women with SZ


Risk Factors: Prenatal

Prenatal infection
o Increase in SZ following a flu epidemic

Exposure to a feline virus increases one’s chance

Rhesus (Rh) incompatibility

Blood types of the mother and child are different

Winter month births
o This trend reflects still-born trends

Some propose the same complication that would kill the fetus may lead to an increased chance of SZ

Poor prenatal care
o Malnutrition and maternal stress

Pregnancy and/or birth complications


Neurodevelopmental factors

Dormant, prenatal, brain lesions only arise during puberty

Disorganized neuroarchitecture

Neurons of the brain are strung together in irregular patterns

Complicated, impractical, tangle


Other Biological Factors

*Note: not all those diagnosed with SZ display these abnormalities

**Abnormalities are not required to diagnosis SZ

Decreased brain volume

Decreased volume of the thalamus
o Thalamus and irregular temporal lobe are linked with hallucinations

Increased ventricles – which is correlated with negative symptoms

Irregularities in the frontal lobe


The dopamine hypothesis:

Dopamine mediates the salience of environmental events and internal representations

Increased DA D2 receptors activity

Complicated link though: blocking D2 may increase D1

Drugs that block dopamine help control symptoms in those with SZ
o But current meds only target D2 receptors and only treat the positive symptoms


Dopamine Hypothesis: Pathways

4 major dopamine pathway, but 2 key in SZ




Flaws to Dopamine Hypothesis

There is no genetic link to dopamine production

There is no consistent therapeutic effect of regulating dopamine


Glutamate Hypothesis

Nearly half of all neurons in the brain and nearly all of them in the cerebral cortex use glutamate

Decreased glutamate leads to negative and cognitive symptoms of SZ, including sensory processing deficits

Early trials of glutamate agonists seem to yield similar results of antipsychotics


Glutamate Hypothesis: NMDA gateway

NMDA(R) (glutamate receptor) antagonists increase negative and cognitive symptoms

Glutamate regulates other neurotransmitters that are affiliated with SZ – NMDA is known as the gateway receptor


SZ Categories of Symptoms


Negative affect

Disorganized speech/behavior

Hospitalization occurs if the individual is a risk to self or others

*Just having the symptoms does not lead to hospitalization



Disturbances in content of thought

Fixed and firmly held despite clear contradictory evidence

Erroneous beliefs


Alien control (aka made impulses)

Thought control

thought broadcast

Grandiosity (though it’s more popular in bipolar)



Sensory experiences that seem real but occur in the absence of any external perceptual stimuli

Can occur in any sensory modality (taste, sight, smell, etc.)

~70% of hallucinations involve auditory hallucinations

10-20% are visual hallucinations
• Which are typically distorted images – not clear-cut

Some evidence hallucinations may be the inability to identify thoughts/ideas as internally-generated
• source monitoring errors


Difference between hallucinations and illusions

Illusions are caused by real-world stimuli

Hallucinations are typically negative


Disorganized Speech

Failure to make sense of speech--despite conforming to semantic and syntactic rules of speech

Includes disturbances in form, not content, of thought

Differs from manic “flight of ideas”
• With flight of ideas, the speech, while confusing, is understandable when broken down


Disorganized Behavior

Impairments of goal-directed activity

Occurs in all areas of daily-functioning

Catatonia – frozen

Catatonia Stupor = cannot be physically moved


Negative Symptoms

Avolition (loss of motivation)

Anhedonia (loss of interest)

Flat affect

Alogia (aka poverty of speech; using few words and a lack of spontaneity)

**Important to note flat affect is in terms of expression
• Independent of internal feelings

Overall loss or decrease in normally-present behaviors


Altered Neurocognitions

Working memory

Attentional functioning

Speech production

Eye tracking

*Degree to which these are dysfunctional are the best predictors of real-life functioning following discharge


Expressed Emotions (E. E.)

Expressed emotions (E.E.) of the families which includes
1. Emotionally overinvolved
2. Overly critical
3. Hostile

Increased EE is related to increased rate of relapse following discharge

In such cases, patient is better living alone following discharge

EE can be reduced via psychoeducation

Some argue that EE may not only encourage relapse, but it can encourage SZ’s appearance in the first place


Risk Factors: Low SES

*SZ 8x more likely in low SES, possibly due to:

Poor nutrition

Lack of access to appropriate healthcare

Increased stress


Schizoaffective Disorder

Includes mood symptoms

But the psychotic symptoms are independent of the mood

If they are dependent, then it’s bipolar or depression with psychotic features


Schizophreniform Disorder

Active symptoms for less than 6 months, with impaired functioning

Typically turns into SZ


Delusional Disorder

Only well-developed delusional symptoms are present, and the individual is still able to function


Shared Psychotic Disorder

When two people share a delusion, not SZ

One is typically the alpha and one is the beta (and follows along)


Brief Psychotic Disorder

Occurs after a traumatic event and naturally fades away

The individual is not likely to have another episode


SZ Treatment: History, Dorothea Dix

Dorothea Dix advocated for better treatments

Increase in psychiatric institutes in the late 19th century in reaction to her work, but there were few treatments

Castration, lobotomy, near-death experiences, hydrotherapy


SZ Treatment: 1950's

Real change began in the 1950s

Creation of the first psychiatric drug – Thorazine

First used to treat allergies

Affects the D2 receptors

Has many side effects including sedation (like most allergy medication)


SZ Treatment: 1960's

Development of Haldol

The Community Mental Health Act – in an attempt to move treatment to the community

*Released many patients from hospitals without building community health centers

*Patients were now on the streets


SZ Treatment: Haldol

Still a high dosage medication but lacked the sedating effects of Thorazine

Had many extrapyramidal symptoms (EPS)

Long term use: risk of tardive dyskinesia


SZ Treatment: Haldol EPS

EPS=movement disorders and tardive-like symptoms

Blocked dopamine receptors throughout the brain, thereby mimicking the symptoms of Parkinson’s

Increase in acetylcholine and norepinephrine :

Muscle rigidity

Slowed movements

Resting tremors

Dystonia (muscles locked)

Akathisia (inability to sit still)

To deal with the side effects, additional drugs were administered to reduce the EPS

Lower ACH and remove the cholinergic effects

Add beta-blocker to decrease norepinephrine and remove akathisia


SZ Treatment: Tardive dyskinesia

Includes spasmodic, gross, motor-movements

Not due to EPS, but rather due to long-term usage of 1st generation antipsychotics

Due to years of chronic dopamine depletion, new, more sensitive, dopamine receptors are created
*More sensitive receptors = more easily fired


SZ Treatment: Late 1980s, early 1990s – development of 2nd generation antipsychotics

2nd generation antipsychotics aka “atypicals”

Atypicals have, generally, less severe side effects, but are no more efficient that 1st generation antipsychotics

Less restrictive on the dopamine systems

Controls the system just enough and then releases hold to reduce symptoms

Clozapine-- "first and best" according to Serper


SZ Treatment: Psychological Approaches

In conjunction with medication:

Family therapy

Case management
• Supervisor is in contact 24 hours a day
• Known as the Assertive Community Model (ACT)

Social skills Treatment
• Difficult to generalize skills however

Cognitive remediation
• Attempt to increase attention and memory by treating the brain like a muscle

Cognitive behavioral therapy
• For delusions and psychosis

Other forms of individual treatment


DA Theory in SZ: L-Dopa

L-dopa and D-amphetamine can cause psychosis-like state in healthy humans and exacerbate symptoms of schizophrenia


DA Theory in SZ: postmortem studies

Postmortem studies showed abnormalities in DA indexed in SZ

*Though data always confounded by drugs


DA Theory in SZ: Neuroimaging Studies

SZ patients when psychotic demonstrate:

Heightened synthesis of DA

Heightened DA release in response to an impulse

Heightened level of synaptic DA


DA Theory in SZ: DA Deficiency

SZ = DA deficiency disorder

Inadequate stimulation of the dopamine D1 receptors

Administration of a D2 antagonist--(blocks DA auto receptors) results in:
*Increased DA release
*Increased stimulation of D1 receptors

Antipsychotic drugs increased the metabolism of DA when administered to animals


DA Theory in SZ: Amphetamines

Amphetamine increases synaptic monoamine levels and can induce psychotic symptoms

Reserpine – effective for treating psychosis – blocks the reuptake of DA and other monoamines

Clinical effectiveness of antipsychotic drugs was directly related to their affinity for DA receptors

*Proposal: excess in dopaminergic neurotransmission


DA Theory in SZ: Abnormal regulation of the DA system

DA mediates the salience of environmental events and internal representations
* e.g. pleasure, reward, reinforcement, prediction error

A dysregulated hyperdopaminergic state leads to stimulus-independent DA release

This leads to an aberrant assignment of salience to one's experience


DA Theory in SZ: Prominence

DA model has been the leading neurochemical hypothesis of SZ for the last 40 years

**Current medications functioned primarily to block DA D2 receptors


Glutamate Theory in SZ

NMDA (Glutamate receptors) agonists produce negative and cognitive symptoms of SZ

Induce neuropsychological and sensory processing deficits

Dysregulation of brain DA systems through changes in Glu mechanisms results in positive symptoms of SZ

Currently no approved medication for negative and cognitive symptoms

NMDA receptors appear to be a potential site for therapeutic intervention in SZ


SZ and affect

Deficits in affective EXPRESSION define the disorder

*Not deficits in affective experience

Lack of affect is poor prognostic indicator

The more affect an individual has, generally, the easier it is to treat the disease
e.g. paranoia is highly treatable due to affective component

Sometimes delusion is grandiose, but person is not grandiose, lacks self-esteem
*this is more likely SZ than manic


Eugen Bleuler

Loose Associations

Threads that run through consciousness that bind together thoughts, actions and behavior

Normals: tightly connected threads
SZ: associations loosen or break, causes a split mind

Split consciouness

Split between thoughts, feelings, behavior



SZ: Monothetic Taxonomy

Bleuler's concept of SZ

One symptom defines a disorder: loose associations
Vaguely defined

Anyone with symptom has disorder

Anyone with disorder has the symptom

*few others:
Selective Mutism

Also possibly PTSD--traumatic event more criterion, but not alone


Bleuler and Kraeplin USA and Europe

SZ dx
1930: 20% in NY and London

1955: 80% NY
still 20% London

Europe: Kraeplin
*dementia praecox dx
*narrow definition

USA: Bleuler
*different construct of SZ
*broad definition
*translated into Enhligh
*expanded Bleuler's definition to ambulatory SZ, process SZ, reactive SZ etc
*lot of people lobotomized were probably OCD, Bipolar, BPD--wide net



Earliest drug used to treat SZ which was originally designed to control blood pressure

Inhibits D2 receptors


DA Pathways: Mesolimbic

Affiliated with reward-related cognitions

Increased activation = positive symptoms of psychosis


DA Pathways: Mesocortical

Affiliated with cognitive control

From the midbrain to the frontal cortex

Decreased activation = negative symptoms and cognitive deficits


DA Pathways: Nigrostriatal

Involved with smooth motor movements

Destruction leads to Parkinson’s


DA Pathways: Tuberoinfundibular

Linked with the pituitary gland

Regulates sex drive


Glutamate Hypothesis: NMDA Antagonists

Recreational use of NMDA antagonists increase SZ-like behavior, both positive and negative symptoms

angel dust



Glutamate Hypothesis: Genetics

Genes affiliated with SZ impact glutamate

More specifically NMDA receptor expression or receptor sites and activation
*especially in the frontal cortex

Increase in enzymes that break down glutamate in those with SZ

Medication-free individuals with SZ display decreased NMDA binding at the hippocampus


SZ and Low SES: Social Drift vs. Social Residual

Social drift – the illness causes one to descend in SES ladder

Social residual – the illness prevents one from ascending this ladder


Tardive dyskinesia

Not due to EPS, but rather due to long-term usage of 1st generation antipsychotics

Due to years of chronic dopamine depletion, new, more sensitive, dopamine receptors are created

More sensitive = more easily fired

Includes spasmodic, gross, motor-movements


2nd generation (atypicals) side effects



Metabolic deregulation

Zyprexa tends to cause the most weight gain

Increase in prolactin release
*alterations of sex characteristics and libido

Agranulocytosis = deadly allergic reaction
o Destroys red blood cells in 1% of those with SZ


DA hypothesis: Salience and Delusions

DA mediates the salience of environmental events and internal representations
* e.g. pleasure, reward, reinforcement, prediction error

A dysregulated hyperdopaminergic state leads to stimulus-independent DA release

This leads to an aberrant assignment of salience to one's experience

Delusions may be cognitive effort by the patient to make sense of these aberrantly salient experiences


DA hypothesis: Salience and Hallucinations

DA mediates the salience of environmental events and internal representations
* e.g. pleasure, reward, reinforcement, prediction error

A dysregulated hyperdopaminergic state leads to stimulus-independent DA release

This leads to an aberrant assignment of salience to one's experience

Hallucinations may reflect the direct experience of the aberrant salience of internal representations

Antipsychotics dampen the salience of these abnormal experiences

If antipsychotic treatment is stopped, the dysregulated neurochemistry returns, and a relapse occurs


DSM-5 Changes in SZ

At least 1 of core "positive symptoms" necessary for dx

Removal of subtypes (paranoid, disorganized, cationic)
*no distinctive pattern of tx response or course