Etiology

Question 1

Biochemical factors headings

Answer 1

1. Dopamine hypothesis
2. Serotonin
3. Norepinephrine
4. GABA
5. Neuropeptides
6. Glutamate
7. Ach and nicotine

Question 2

Headings in etiology

Answer 2

1. Genetic factors
2. Biochemical factors
3. Neuropathology
4. NeuraL circuits
5. Brain metabolism
6. Applied electrophysiology
7. Eye movt dysfunction
8. Psychoneuroimmunology
9. Psychoneuroendocrinology
   10 psychosocial amd psychoanalytic theories
   11 family dynamics

Question 3

Dopamine hypothesis

Answer 3

schizophrenia results from too much dopaminergic activity based on two observations.:
1. AP act on D2, symptom relief
2. Drugs increasing dopamine cause psychosis

Position emission tomography studies of dopamine receptors document an increase in D2 receptors in the caudate nucleus of drug-free patients with schizophrenia

increased dopamine concentration in the amygdala, decreased density of the dopamine transporter, and increased numbers of dopamine type 4 receptors in the entorhinal cortex

4. Tuberoinfundibular: hyperprolactenimia
5. Nigrostiatal: motor
6. Mesolimbic: positive
7. Meso cortical: negative

Question 4

Serotonin

Answer 4

serotonin excess as a cause of both positive and negative symptoms in schizophrenia.

serotonin antagonist activity of clozapine and other second-generation antipsychotics coupled with the effectiveness of clozapine to decrease positive symptoms in chronic patients has contributed to the validity of this proposition.

Question 5

Norepinephrine

Answer 5

selective neuronal degeneration within the norepinephrine reward neu­ ral system could account for this aspect of schizophrenic symptomatol­ ogy.

Question 6

GABA

Answer 6

loss of GABAergic neurons in the hippocampus. GABA has a regula­ tory effect on dopamine activity, and the loss of inhibitory GABAergic neurons could lead to the hyperactivity of dopaminergic neurons.

Question 7

Neuropeptides

Answer 7

Neuropeptides, such as substance P and neuro­ tensin, are localized with the catecholamine and indolamine neurotrans­ mitters and influence the action ofthese neurotransmitters. Alteration in neuropeptide mechanisms could facilitate, inhibit, or otherwise alter the pattern of firing these neuronal systems.

Question 8

Glutamate

Answer 8

hyperactivity, hypoactivity, and glutamate-induced neurotoxicity.

Question 9

Acetylcholine and Nicotine.

Answer 9

Postmortem studies in schizo­ phrenia have demonstrated decreased muscarinic and nicotinic receptors in the caudate-putamen, hippocampus, and selected regions of the pre­ frontal cortex. These receptors play a role in the regulation ofneurotrans­ mitter systems involved in cognition, which is impaired in schizophrenia.

Question 10

Neuropathology headings

Answer 10

1. Pruning
2. Cerebral ventricles
3. Reduced symmetry
4. Limbic . System
5. PFC
6. Thalamus
7. Basal ganglia and cerebellum

Question 11

Pruning

Answer 11

Synaptic density is highest at age 1 year and then is pared down to adult values in early adolescence. One theory, based in part on the observation that patients often develop schizophrenic symptoms during ado­ lescence, holds that schizophrenia results from excessive prun­ ing of synapses during this phase of development.

Question 12

Cerebral ventricles

Answer 12

Ct: lateral and 3rd ventricle enlargement, reduction in cortical volume

Question 13

Reduced symmetry

Answer 13

In temporal, frontal, and occipital lobes. This reduced symem try is believed by some investigators to originate during fetal life and to be indicative of a disruption in brain lateralization during neurodevelopmen

Question 14

Limbic system

Answer 14

Controls emotions

a decrease in the size ofthe region, including the amygdala, the hippocampus, and the parahippocampal gyrus .

hippocampus is not only smaller in size in schizophrenia but is also functionally abnormal as indicated by disturbances in glutamate transmis­ sion.

Question 15

PFC

Answer 15

Anatomical and fxnal deficits

Question 16

Thalamus

Answer 16

1. Volume shrinkage and neuronal loss
2. The medial dorsal nucleus of the thalamus, which has recipro­ cal connections with the prefrontal cortex, has been reported to contain a reduced number of neurons

Question 17

Basal ganglia and cerebellum

Answer 17

1. many patients with schizophre­ nia show odd movements, even in the absence of medication­ induced movement disorders (e. Including awkward movements, grimacing, stereotypies
2. movement disorders involving the basal ganglia (e.g., Hunting­ ton’s disease, Parkinson’s disease) are the ones most commonly associated with psychos
3. n increase in the number of D2 receptors in the caudate, the putamen, and the nucleus accumbens

Question 18

Neural circuits

Answer 18

1. dysfunction of the anterior cingulate basal ganglia thalamo­ cortical circuit underlies the production of positive psychotic symptoms, dysfunction of the dorsolateral prefrontal circuit underliestheproductionofprimary,enduring,negativeordef­ icit symptoms.
2. impaired working memory performance, disrupted prefrontal neuronal integrity, altered prefrontal, cingulate, and inferior parietal cortex, and altered hippocampal blood flow provides strong support for disrup­ tion of the normal working memory neural circuit in patients with schizophrenia.

Question 19

Brain metabolism

Answer 19

MR spectroscopy : lower levels of phos­ phomonoester and inorganic phosphate and higher levels ofphos­ phodiester than a control group. Furthermore, concentrations of N-acetyl aspartate, a marker ofneurons, were lower in the hippo­ campus and frontal lobes ofpatients with schizophrenia.

Question 20

Applied Electrophysiolog

Answer 20

1. increased sensitivity to activation procedures (e.g., frequent spike activity after sleep deprivation), decreased alpha activity, increased theta and delta activity, possibly more epileptiform activity than usual, and pos­ sibly more left-sided abnormalities than usual
2. an inability to filter out irrelevant sounds and are extremely sensitive to background noise. The flooding of sound that results makes concentration difficult and may be a factor in the production of auditory hallucinations. This sound
   sensitivity may be associated with a genetic defect.
3. Complex partial seizures: Factors associated with the devel­ opment of psychosis in these patients include a left-sided sei­ zurefocus,medialtemporallocationofthelesion,andanearly onset of seizures.
4. Evoked Potentials.

The P300 has been most studied and is defined as a large, positive evoked-potential wave that occurs about 300 mil­ liseconds after a sensory stimulus is detected. The major source ofthe P300 wave may be located in the limbic system structures ofthe medial temporal lobes. In patients with schizophrenia, the P300 has been reported to be statistically smaller than in com­ parison groups.

N 100 also implicated

Question 21

Eye movement dysfunction

Answer 21

The inability to follow a moving visual target accurately is the defining basis for the disorders of smooth visual pursuit and disin­ hibition of saccadic eye movements seen in patients with schizo­ phrenia. Eye movement dysfunction may be a trait marker for schizophrenia;

abnormal eye movements in 50 to 85 percent ofpatients with schizophrenia compared with about 25 percent in psychiatric patients without schizophrenia and
fewer than 1 0 percent in nonpsychiatrically ill control participan

Question 22

Psychoneuroimmunology

Answer 22

decreased T-cell interleukin-2 production, reduced number and responsiveness of peripheral lymphocytes, abnormal cellular and humoral reactivity to neurons, and the presence of brain­ directed (antibrain) antibodies.

viral hypothesis are an increased number of physical anomalies at birth, an increased rate of pregnancy and birth complications, seasonality of birth consistent with viral infection, geographical clusters of adult cases, and seasonality of hospitalizations.

Question 23

Psychoneuroendocrinology

Answer 23

persistent nonsuppre ssion on the dexamethasone- suppre ssion test in
schizophrenia with a poor long-term outcome.

decreased concentrations of luteinizing hormone or follicle-stimulating hormone, perhaps correlated with age of onset and length of illnes

e presence of negative
symptoms: a blunted release of prolactin and growth hormone on gonadotropin-releasing hormone or thyrotropin-releasing hormone stimulation and a blunted release of growth hormone on apomorphine stimulation

Question 24

Psychoanalytic Theories.

Answer 24

1. Sigmund Freud postulated that schizophrenia resulted from developmental fixations early in life.

Ego disintegration in schizophrenia represents a return to the time when the ego was not yet developed or had just begun to be established. Because the ego afef cts the interpretation of reality and the control of inner drives, such as sex and aggression, these ego functions are impaired. Thus, intrapsychic con­ flict arising from the early fixations and the ego defect, which may have resulted from poor early object relations, fuel the psychotic symptoms.

2. Margaret Mahler, there are distortions in the reciprocal relationship between the infant and the mother. The child is unable to separate from, and progress beyond, the closeness and complete dependence that characterize the mother-child relationship in the oral phase of development. As a result, the person’s identity never becomes secure.
3. Paul Federn hypothesized that the defect in ego functions permits intense hostility and aggression to distort the mother-infant relation­ ship, which leads to eventual personality disorganization and vulnera­ bility to stress.
4. Harry Stack Sullivan viewed schizophrenia as a disturbance in inter­ personal relatedness. The patient’s massive anxiety creates a sense of unrelatedness that is transformed into parataxic distortions, which are usually, but not always, persecutory. To Sullivan, schizophrenia is an adaptive method used to avoid panic, terror, and disintegration of the sense of self. The source of pathological anxiety results from cumulative experiential traumas during development.
5. t the various symptoms of schizophrenia have symbolic meaning for individu al patients. For exam­ ple, fantasies of the world coming to an end may indicate a perception
   that a person’s internal world has broken down. Feelings of inferiority are replaced by delusions of grandeur and omnipotence.

Question 25

Learning theories

Answer 25

children who later have schizophrenia learn irrational reactions and ways of thinking by imitating parents who have their own significant emotional problems. In learning theory, the poor interpersonal relationships ofper­ sons with schizophrenia develop because of poor models for learning during childhood.

Question 26

Family dynamics

Answer 26

1. The double-bind concept was formulated by Greg­ ory Bateson and Donald Jackson to describe a hypothetical family in which children receive conflicting parental messages about their behav­ ior, attitudes, and feelings. In Bateson’s hypothesis, children withdraw into a psychotic state to escape the unsolvable confusion of the double bind.

An example of a double bind is a parent who tells a child to provide cookies for his or her friends and then chastises the child for giving away too many cookies to playmates.

2. Schisms and Skewed Families. Theodore Lidz described two abnormal patterns of family behavior. In one family type, with a prominent schism between the parents, one parent is overly close to a child of the opposite gender. In the other family type, a skewed relationship between a child and one parent involves a power struggle between the parents and the resulting dominance of one parent.
3. Pseudomutual and Pseudohostile Families. As described by Lyman Wynne, some families suppress emotional expres­ sion by consistently using pseudomutual or pseudohostile verbal com­ munication. In such families, a unique verbal communication develops, and when a child leaves home and must relate to other persons, prob­ lems may arise. The child’s verbal communication may be incompre­ hensible to outsiders.
4. Expressed emotions

Question 27

Genetics headings

Answer 27

1. Family studies
2. Twin studies
3. Adoption studies
4. GWAS
5. CNVs
6. Pleiotropy
7. Risk counseling

Question 28

Gottesman and Shields (1982)
Morbidity risk : general population

Answer 28

1%

Question 29

Gottesman and Shields (1982)
Morbidity risk : first cousins and uncles/ aunts

Answer 29

2.4%

Question 30

Gottesman and Shields (1982)
Morbidity risk : nieces and nephew

Answer 30

3%

Question 31

Gottesman and Shields (1982)
Morbidity risk grandchildren

Answer 31

3.7%

Question 32

Gottesman and Shields (1982)
Morbidity risk half siblings

Answer 32

4.2%

Question 33

Gottesman and Shields (1982)
Morbidity risk parents

Answer 33

5.6%

Question 34

Gottesman and Shields (1982)
Morbidity risk
All siblings

Answer 34

10.1#

Question 35

Gottesman and Shields (1982)
Morbidity risk : siblings (parents weLl ) and one parent schiz

Answer 35

9.6, 16.7

Question 36

Gottesman and Shields (1982)
Morbidity risk
Children
Children with both parents schiz

Answer 36

12.8 and 46.3%

Question 37

Morbidity risk for schizophrenia in the old and the newer family in siblings

Answer 37

Old 10.1
New 7.4

Question 38

Morbidity risk for schizophrenia in the old and the newer family in parents

Answer 38

Old 5.6
New 2.3

Question 39

Morbidity risk for schizophrenia in the old and the newer family in children

Answer 39

Old 12.9
New 15.0

Question 40

two methods of estimating the concordance rate In twin studies

Answer 40

In the pairwise method, concordance is simply the number of concordant pairs divided by the total number (e.g., if five pairs of twins are affected and in each of another five pairs, only one twin is affected, the pairwise concordance rate is 5/10 = 50 percent). In the probandwise method, if both members of a pair were ascertained independently (i.e., they are both probands), the pair is counted twice because each of these probands has an affected co-twin.

Question 41

Identical Twins Reared Apart

Answer 41

Gottesman and Shield

This gives a pairwise concordance (64 percent) that is higher than that for twins reared together.

Question 42

Gottesman ans Shield heritability estimates twin studies schiz

Answer 42

between 53 percent and 90 percent,
2 meta analysis providing estimates between 81 and 88 %

Question 43

Identical Twins Reared Apart

Answer 43

Avoids shortcomings of shared environment assumption

Gottesman and Shields described fourteen pairs of MZ twins reared apart, nine of whom were concordant for schizophrenia. This gives a pairwise concordance (64 percent) that is higher than that for twins reared together.

Question 44

The Offspring of Twins Discordant for Schizophrenia:
There are two possible explanations for discordance of a heritable disorder in MZ twins.

Answer 44

The first is that the affected twin suffers from an environmentally determined form of the disorder (termed a phenocopy). The second is that both twins inherited the same increased genetic liability but that this is expressed only in the affected twin.

Question 45

The Offspring of Twins Discordant for Schizophrenia: rates

Answer 45

1. One study, In 11 twins with schiz, 16.8 % risk and 6 unaffected cotwins- m offsprings, 17.4% risk
2. Another study, offspring of twins with schiz (10,7% risk) and 2.2 % risk In unaffected twins

Question 46

Adoption studies

Answer 46

1. Children of parents with schizophrenia have at least a 10 percent risk of developing schizophrenia, schizoaffective disorder, or other narrow-spectrum schizophrenic disorder when adopted away very soon after birth.
2. Rosenthal (1971),
   Denmark: 26.9% of 52 children of SZ Parents developed schiz spectrum illness
3. Lichtenstein et al, 2009: Adopted away children of affected parents had a relative risk of schizophrenia of 13.7

Question 47

The largest and most successful schizophrenia GWA studies to date were conducted

Answer 47

by the Psychiatric Genomics Consortium

Question 48

Psychiatric genomics consortium GWAS results

Answer 48

1. discovered 128 independent SNPs at 108 loci that exceeded genome-wide significance (P <5 × 10−8) for association with schizophrenia.
2. 75 % of these loci included protein coding genes and 8% were within 20 kilo base of a gene
3. Genes: (dopamine) DRD2, (glutamate) GRM3, GRIN2A, SRR, GRIA1 and ( calcium signaling) CACNA1C, CACNB2, and CACNA1I).

Question 49

What are CNVs

Answer 49

CNVs are deletions or duplications of chromosomes of at least 1 kb in size.

Question 50

CNVs and Schizophrenia

Answer 50

1. deletion of about 2.5 Mb on chromosome 22q11.2 (80%)

Carriers of this CNV were shown to have up to 30 percent risk of
developing schizophrenia or other psychotic disorders.

2. As of today, there are 12 CNVs in 11 loci that have reached the
   accepted genome-wide levels of statistical significance of P value of <4.1 × 10−4.
3. NRXN1 gene : It codes for a cell adhesion molecule, neurexin 1, which is specific to synapses in the brain, where it mediates interactions between pre- and postsynaptic structures.
4. 1q21.1 deletion (30%) and duplication (20%)
5. 3q29 del(50%)
6. 15q11.2 del (10%)
7. 16p11.2 del and dup(25%)
8. Angel an/ Prader willi dup (50-60%)

These also increase the risk of developing intellectual deficit, developmental delay, autism spectrum disorders, and various congenital malformations and somatic diseases.

Question 51

Epidemiology headings

Answer 51

1. Gender and age
2. Reproductive factors
3. Medical illmess
4. Infection and birth season
5. Population density
6. Substance abuse
   7 socioeconomic and cuLtiral factors

Question 52

Gender and age

Answer 52

1. Male = female
2. Onset earlier In men
   3 More than half of all male schizo­ phrenia patients,
3. but only one-third of all female schizophrenia patients, are first admitted to a psychiatric hospital before age 25 years.
4. The peak ages of onset are 1 0 to 25 years for men and 25 to 35 years for women. Unlike men, women display a bimodal age distribution, with a second peak occurg in middle age.
5. Approximately 3 to 10 percent of women with schizophrenia present with disease onset after age 40 years.
6. About 90 percent ofpatients in treatment for schizophrenia are between 15 and 55 years old.
7. men are more likely to be impaired by negative symptoms (described later) than are women and that women are more likely to have bet­ ter social functioning than are men before disease onse

Question 53

Medical illmess

Answer 53

Higher mortality due to accidents and natural causes

up to 80 percent of all schizophrenia patients have significant concurrent medical illnesses and that
up to 50 percent ofthese conditions may be undiagnosed.

Question 54

Infection and Birth Season

Answer 54

born in the winter and early spring and less likely to have been born in late spring and sumem r.

North hemisphere jan to apr
South hemisphere July to sep

gestational and birth complications, exposure to influenza epidemics, maternal starvation during pregnancy, Rhesus factor incompatibility, and an excess of win­ ter births in the etiology of schizophrenia.

Prenatal exposure to influenza

Question 55

Population density

Answer 55

More Im cities with > 1 million people

the incidence of schizophrenia in children of either one or two parents with schizophrenia is twice as high in cities as in rural communities.

Question 56

Socioeconomic and cultural factors

Answer 56

Socioeconomic and Cultural Factors
Economics. Because schizophrenia begins early in life; causes significant and long-lasting impairments; makes heavy demands for hospital care; and requires ongoing clinical care, rehabilitation, and support services,

Hospitalisation

Even with antipsychotic medication, however, the probability of readmis­ sion within 2 years after discharge from the first hospitalization is about 40 to 60 percent. Patients with schizophrenia occupy about 50 percent of all mental hospital beds and account for about 16 percent of all psychiatric patients who receive any treatment

Question 57

Substance Abuse

Answer 57

1. The lifetime prevalence of any drug abuse (other than tobacco) is often greater than 50 percent.
2. Poorer function
3. the lifetime prevalence of alcohol within schizophrenia was 40 percent. Alcohol abuse increases risk of hospitalization and, in some patients, may increase psychotic symptoms.
4. Those reporting high levels ofcannabis use (more than 50 occa­ sions) were at sixfold increased risk of schizophrenia compared with nonusers

Question 58

Nicotine

Answer 58

1. Upto 90 % have TDS
2. DECREASES blood concentration of antipsychotics
   3l brain abnormalities in nicotine receptors
3. specific poly­ morphism in a nicotinic receptor has been linked to a genetic risk for schizophrenia.
4. improve some cogni­ tive impairments and parkinsonism in schizophrenia, possibly because of nicotine-dependent activation of dopamine neurons.
5. Decreases pos symptoms
6. Reduced perception of outside stimuli especially noise
7. Self medication