Schizophrenia

what are the types of schizophrenia symptoms?

• positive, negative, cognitive

• symptom onset is usually in early adulthood

• appear gradually over a period of 3-5 years

• negative symptoms appear first, followed by cognitive then positive

positive symptoms

• make themselves known by their presence (excess)

• they include thought disorders, delusions and hallucinations

what are thought disorders?

• disorganized, irrational thinking – probably the most important symptom of schizophrenia

• great difficulty arranging thoughts logically, and sorting out plausible conclusions from absurd ones.

• during conversation they jump from one topic to another as new associations come up.

• sometimes utter meaningless words or choose words for rhyme rather than for meaning

what are delusions?

• beliefs that are contrary to fact; there are many types:

  • persecution - false beliefs that others are plotting and conspiring against oneself

  • grandeur - false beliefs about one’s power and importance

  • control - related to persecution; the person believes that they are being controlled by others through radar or a radio receiver implanted in their brain

what are hallucinations?

• perceptions of stimuli that are not actually present

• most common are auditory but they can involve any of the other senses

• olfactory hallucination are also fairly common and often contribute to the delusion that others are trying to kill them

negative symptoms

• known by they absence or diminution of normal behaviours

cognitive symptoms

include:

• difficulty in sustaining attention

• low psychomotor speed

• deficits in learning and memory

• poor abstract thinking

• poor problem solving

cognitive symptoms in the brain

• all neurocognitive deficits are associated with frontal lobe hypofunction

• Weinberger (1988) suggested that the negative symptoms of schizophrenia are caused primarily by hypofrontality, decreased activity of the frontal lobes, the dlPFC in particular

the stroop task

• involves naming the colour of the ink in two conditions: congruent and incongruent

• schizophrenia patients are slower and less accurate

the Wisconsin card sort test

• normally during the task there is an increase in regional blood flow to the dlPFC

• not seen in schizophrenia patients

sensory-motor gating deficits

• difficulties screening out irrelevant

• pre-pulse inhibition (PPI)

• when a weak stimulus precedes a startle stimulus by approx. 100ms, the normal response is to inhibit the startle

• people with schizophrenia do not inhibit the startle

oculomotor function

• smooth pursuit - tracking a moving stimulus

• the eye movements of schizophrenia patients are not smooth compared to controls

structural differences

• Weinberg and Wyatt (1982) - CT scans of schizophrenics and healthy controls of the lateral ventricles

• the relative ventricle size of the schizophrenic patients was more than twice as big as that of normal control subjects

• reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampus

• faulty cellular arrangement in the cortex and hippocampus

heritability and genetics

• adoption and twin studies indicate that schizophrenia is a heritable trait but is not due to a single dominant or recessive gene

• having a “schizophrenia gene” causes a susceptibility to develop schizophrenia which may be triggered by environmental factors

genetics of schizophrenia

• one rare mutation involves a gene called DISC1 (disrupted in schizophrenia 1)

• involved in the regulation of neurogenesis, neuronal migration, postsynaptic density in excitatory neurons, and mitochondria function

• appears to increase the chance of schizophrenia by a factor of 50

paternal age

• the children of older fathers are more likely to develop schizophrenia

• most likely due to mutations in the spermatocytes

twins studies

• the concordance rate for monochorionic MZ twins was found to be 60% vs 32% in dichorionic MZ twins

the ‘early’ neurodevelopmental model

• Events in early life (prenatally) cause deviations from normal neurodevelopment and these lie dormant until the brain matures sufficiently to call into operation the affected systems (Murray & Lewis, 1987)

• Early events such as infections, obstetric complications, nutritional deficiencies etc. provide evidence in support of this theory

the ‘late’ neurodevelopmental model

• schizophrenia may result from an abnormality or deviation in adolescence when synaptic pruning takes place

‘two-hit’ model

• atypical development in schizophrenia takes place during 2 critical time points: early brain development and adolescence

• early developmental insults may lead to dysfunction of specific neuronal networks that would account for premorbid signs

• during adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms

the dopamine (DA) hypothesis

• Proposes the schizophrenia is caused by abnormalities in DA functioning in the brain

• Overactivity of DA in the mesolimbic system results in the positive symptoms of schizophrenia

• Underactivity of DA in the mesocortical system results in the negative and cognitive symptoms of schizophrenia

DA agonists induce psychosis (evidence for DA hypothesis)

• DA agonists produce symptoms that resemble the positive symptoms of schizophrenia.

• These drugs include amphetamine, cocaine, methylphenidate and L-DOPA.

• The symptoms that they produce can be alleviated with antipsychotic drugs

  strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking DA receptors

DA antagonists (evidence for the DA hypothesis)

• Henri Laborit (mid 20^thce): French surgeon who discovered that a drug used to prevent surgical shock also reduced anxiety

• A related compound called chlorpromazine (CPZ) was developed in 1952 which had dramatic effects on schizophrenia.

• CPZ is a DA antagonist – first antipsychotic

antipsychotic drugs (evidence for the DA hypothesis)

• Since the discovery of CPZ, many drugs have been developed for the treatment of schizophrenia – typical antipsychotics

• Two major families of DA receptors:

  • D1-type family (Gs coupled): D₁ & D₅

  • D2-type family (Gi coupled): D₂, D₃, D₄

• These drugs have one property in common: They block D₂ receptors

treatment with typical antipsychotics

• these drugs eliminate/diminish the positive symptoms in most of the patients (about 20-30%) do not respond to these drugs

• long-term treatment leads to at least some symptoms resembling those in Parkinson’s disease - slowness in movement, lack of facial expression and general weakness

• a more serious side effect develops in approx. 1/3 of all patients who took the drugs for an extended period - tardive dyskinesia (unable to stop moving)

newer drugs - treatment with atypical antipsychotics

• they work in treatment-resistant patients

• atypical do not have the Parkinsonian side-effects due to their lower affinity for the D2 receptors

• improve both positive and negative symptoms of schizophrenia

• also improve the performance in neurotypical tests which is not the case with typical antipsychotics

clozapine

• first of the atypical antipsychotic drugs

• Has lower affinity for D₂ and higher affinity for other DA receptors (D₃, D₄ and even 5HT)

• Although it is highly effective it is still not widely used – despite international consensus to use it when other drugs have failed

• The only antipsychotic to reduce suicide rates in schizophrenics

• Still considered to be tricky due to its side effects: weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia etc

problems with the dopamine hypothesis

• It explains only a part of schizophrenia (positive symptoms not negative symptoms)

• Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better antipsychotics

• Negative symptoms are caused by under-activity in the mesocortical dopamine pathway

• So, dopamine underactivity is the problem rather than dopamine overactivity

the glutamate hypothesis of schizophrenia

• glutamate is the major excitatory neurotransmitter in the central nervous system and the most prevalent one

• many neurons in the brain use glutamate as their neurotransmitter

• In mammalian brains, glutamate is balanced with GABA (main inhibitory chemical transmitter)

• Both neurotransmitters influence almost every other chemical and brain area

• Evidence implicates NMDA receptors in schizophrenia

NMDA and schizophrenia

• NMDA receptors comprise a critical component of development processes which include:

  • •Development of neural pathways

    •Neural migration

    •Neural survival

    •Neural plasticity

    •Neural pruning of cortical connections

    •Apoptosis

glutamate hypo-functioning hypothesis (Olney and Farber, 1995)

Schizophrenia is due to NMDA receptor hypofunction which may explain:

• Why there are so many treatment-resistant negative symptoms

• Why the onset is in early adulthood

• Why the disorder is associated with structural changes and cognitive deficits.

evidence for the glutamate hypo-functioning hypothesis

• The drugs Phencyclidine (PCP, also known as “angel dust”) and ketamine (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia

• Both of them are NMDA receptor antagonists

• Glutamate agonists seem to improve both positive and negative symptoms of schizophrenia

• Evidence in support from animal genetic studies with NMDA receptor subunits as well as GWAS

positive and negative symptoms: role of the PFC

• The negative and cognitive symptoms produced by ketamine and PCP are caused by a decrease in the metabolic activity of the frontal lobes.

• Jentsch et al. (1997) administered PCP to monkeys twice a day for two weeks.

  • A week later, tested the animals on a task that involved reaching around a barrier for a piece of food

  • Performance depends on the function of the PFC (animals with lesions of the PFC perform poorly).

  • Control monkeys performed well, but those treated with PCP showed a severe deficit

hypo-functioning NMDA receptors theory

• This theory is more comprehensive - it can explain the positive, negative & cognitive symptoms of schizophrenia

• It accounts for the lack of effectiveness of DA antagonists in treating schizophrenia

• Hypo-functioning NMDA receptors can account for both the excessive DA release in the mesolimbic DA system as well as the reduced release of DA in the prefrontal cortex

microglial activation and schizophrenia (neuroinflammatory hypothesis of schizophrenia)

• The brain’s immune cells are hyperactive in people who are at risk of developing schizophrenia

• Many animals studies show a link between pro-inflammatory agents and schizophrenia symptoms 

• The symptoms are reversed upon treatment with antipsychotics or treatment with antibiotics that reduce microglial activation

• Support the evidence for prenatal or perinatal infection and the increased risk for schizophrenia

recent genome-wide association studies of schizophrenia

• Identified 100+ genetic loci that contribute to schizophrenia risk.

• The dopamine-receptor gene, DRD2, GLU receptor subunits etc are associated with risk of schizophrenia

• Most significant association is on chromosome 6 which includes a region of genes involved in acquired immunity (major histocompatibility complex - MHC)

microglia

• In healthy conditions they are in a ramified state and survey the brain for pathogens or debris

• Upon identification of a threat they become activated (amoeboid morphology)

• Their function goes beyond the immune system – involved in a range of homeostatic functions in a healthy brain such as:

  •Neuronal cell death and survival

  •Synaptogenesis

  •Synaptic pruning etc

microglial activation and schizophrenia in animal studies

• microglial activation is not instantaneous in response to infectious agents

• a pre- or perinatal infection primes microglia and this priming may interact with cells in the developing nervous system

• may lead to subtle rearrangement of synaptic circuitry resulting in behavioural impairment in adolescence

oestrogen hypothesis of schizophrenia

• Estrogen is the primary “female” sex hormone with 17β-estradiol being the most potent form

• 17β-estradiol is secreted mainly by the ovaries, fat, breasts and the brain (neuroprotective effect)

• In women there is a 2^nd peak onset of schizophrenia at age 45-50y (menopause)

• Estrogen seems to play a protective role against the development of schizophrenia (buffer)