Lecture 12: Schizophrenia

Question 1

What are psychiatric disorders?

Answer 1

Psychiatric disorders: Disorders of psychological function sufficient to require treatment by a psychiatrist of clinical psychologist

Question 2

How do psychiatric disorders differ from neuropsychological disorders?

Answer 2

No clear cut differences.

Neuropathological disorders were assumed to be products of dysfunctional brains (biological structures); psychiatric disorders were assumed to be products of dysfunctional minds in the absence of brain pathology (emergent property of the brain).

No longer believed to be the case that only neuropathological disorders are the result of dysfunctional brains (also psychiatric).

Psychiatric tend to be influenced more by experiential factors like stress.

Question 3

How are psychiatric disorders diagnosed?

Answer 3

Difficult - Psychiatrist judges whether a person is at the extremes of normality or has a psychiatric disorder. Then the particular disorder, guided by the DSM - provides general diagnostic guidelines.

The psychiatric disorders in the DSM and their diagnoses should be regarded as the current best guidelines rather than real pathological entities.

Question 4

1: Symptoms and incidence

What is schizophrenia?

Answer 4

Means ‘splitting of psychic functions’. Schizophrenia is the disease most commonly associated with madness.

Effects 1% of the population.

Originally thought to be a breakdown of integration between emotion, thought and action.

Hard to define, symptoms overlap with other disorders and change as the disorder progresses. Current definition of schizophrenia likely includes several different brain diseases, some experts refer to the disorder as “the schizophrenias”.

Question 5

1: Symptoms and incidence

Symptoms and diagnosis

Answer 5

Symptoms:

Not all symptoms will appear in all cases. The recurrence of 2 symptoms for one month, or just one that is particularly severe, constitutes grounds for diagnosis.

Symptoms can be seen as ‘positive’ or ‘negative’.

Positive symptoms – hallucinations, psychosis etc (adding to reality). Negative symptoms – social isolation, depression etc (taking away from reality).

Question 6

1: Symptoms and incidence

Symptom list

Answer 6

Bizarre delusions - Can include delusions of being controlled, of persecution, of grandeur

Inappropriate affect (emotions) - Failure to react in appropriate ways (‘normal’ levels of emotion) to positive or negative events

Hallucinations - Imaginary voices telling them what to do or commenting negatively on their behaviour

Incoherent thought - Illogical thinking, peculiar associations among ideas, or belief in supernatural forces

Odd Behaviour - Long periods of no movement (catatonia), lack of personal hygiene, talking in rhymes, avoiding social interaction, echolalia

MORE SPECIFIC SYMPTOMS

Catatonia - going for long periods with no movement

Waxy flexibility - symptom where they react to movement like a mannequin, and can be moved and retain position until moved again

Echolalia - symptom displaying vocalised repetition of some or all of what has just been heard (can also be observed in patients with autism, Tourette’s and disorders of growth)

Question 7

2: What causes schizophrenia?

Historic theories

Answer 7

R.D Laing – author/ ‘antipsychologist’, thought schizophrenia was a myth, a label was just a societal label for people who didn’t fit norms, analysed family interactions between kids and parents (had poor scientific method)

Freud – said paranoid delusions were a result of “repressed homosexual urges which are striving for expression”

Question 8

2: What causes schizophrenia?

Genetic factors

Answer 8

45% concordance rate for identical twins (i.e.<100%) must be other factors…

Adoption studies have shown that the risk of schizophrenia is increased by the presence of the disorder in biological parents, but not by its presence in adoptive parents. So, there is a genetic foundation, but as concordance rates =/ 100%, there must also be environmental factors influencing the disorders development.

Question 9

2: What causes schizophrenia?

Environmental factors

Answer 9

A variety of early experiential factors have been linked to schizophrenia development, for example;

• Birth complications
• Early infections
• Autoimmune reactions
• Toxins
• Traumatic injury.

Question 10

2: What causes schizophrenia?

Environmental factors

Stress

Answer 10

STRESS - exposure to stressors is common before an episode and there is a correlation between the amount of stress and severity of episode

Specific Environmental Stressors: Bullying

The effect of severity and frequency of peer victimisation on overall CAPE frequency scores. CAPE – community assessment of psychic experience

Scores increase with increasing severity and frequency of peer victimisation

Question 11

3: Pharmacolgical treatments

The first anti-psychotic drugs were discovered by luck…

Answer 11

Chlorpromazine – Discovered in the 1950s, originally marketed as an anti-histamine. French surgeon noticed it calmed normal patients when used as anti-inflammatory. When used on schizophrenic patients, it calms those who are agitated and activates those who are emotionally blunted.

Doesn’t cure schizophrenia – just alleviates symptoms to allow people to be discharged.

Reserpine - Taken from snake root plant. Used to treat mental illness in India - also effective in treating schizophrenia. No longer used as it creates a dangerous decline in blood pressure at the doses necessary for treatment.

Question 12

3: Pharmacolgical treatments

Similarities between chlorpromazine and reserpine (despite differing in chemical structure)

Answer 12

• Both take 2-3 weeks of medication to work.
• Symptoms like those in Parkinson’s disease start to emerge (tremors at rest, muscular rigidity, general decrease in voluntary movement)
• It was then discovered that Parkinson’s disease was due to a loss of DOPAMINE (DA) in the nigro-striatal pathway.

Question 13

4: The dopamine hypothesis

What is the dopamine hypothesis?

Answer 13

The theory that schizophrenia is caused by too much dopamine, and, conversely, that anti-schizophrenic drugs work by decreasing dopamine levels

Question 14

4: The dopamine hypothesis

Dopamine (DA): Mode of Action

Answer 14

The two dopaminergic pathways are:

• nigrostriatal pathway
• the mesolimbic and memocortical projections

So dopamine is a neurotransmitter that moves via synaptic conduction…

• reserpine depletes vesicles so reduces amount of DA released into synapse
• chloropromazapine blocks DA receptors so DA cannot function to act on neurons

Question 15

4: The dopamine hypothesis

Things we know support the DA hypothesis…

The way chloropromazine and reserpine work

Answer 15

Chlorpromazine
Acts as a false transmitter (dopamine antagonist). It binds to DA/ dopamine receptors but has no effect (doesn’t activate the receptors) but blocks DA binding to receptors – so DA cannot work properly.

Reserpine
Depletes the brain of DA by breaking down synaptic vesicles in which neurotransmitters (like dopamine) are stored

Question 16

4: The dopamine hypothesis

Things we know support the DA hypothesis…

Drugs like cocaine and amphetamines

Answer 16

These drugs can trigger schizophrenic episodes in normal subjects, known to increase extracellular levels of dopamine and other monoamines as both drugs block reuptake of dopamine, leaving more in the synapse to trigger psychosis.

Monoamines – compounds that have a single amine group in its molecule, especially one which is a neurotransmitter (e.g. dopamine, serotonin, noradrenaline).

Question 17

4: The dopamine hypothesis

Things we know support the DA hypothesis…

Carlsson and Lindqvist

Answer 17

Carlsson and Lindqvist –

Assessed the effects of chlorpromazine on extracellular levels of dopamine and it’s metabolite, found that extracellular levels of dopamine remained the same and it’s metabolite levels increased (this is not what they expected, they expected chlorpromazine to work in the same way as reserpine, depleting the brain of dopamine).

Argued that chlorpromazine is a receptor blocker. Further suggested that the lack of activity in the postsynaptic dopamine receptors sends a feedback signal to the pre-synaptic cells to release more dopamine, which is broken down in the synapse. This explained why dopaminergic activity reduced, while extracellular levels of dopamine stayed about the same, and the extracellular levels of its metabolites increased.

Metabolite – molecules that are created when another molecule is broken down

Revision of the DA theory: Rather than high dopamine levels per se, the main factor in schizophrenia was presumed to be high levels of activity at dopamine receptors.

Question 18

4: The dopamine hypothesis

Summary: Dopamine (DA) theory of cause of Schizophrenia

Answer 18

• Drugs that reduce dopamine neurotransmission reduce psychotic symptoms.
• Drugs that increase dopamine neurotransmission can produce psychotic symptoms.
• This led to the dopamine theory of schizophrenia - it is high levels of activity at dopamine receptors that causes the issues

Question 19

4: The dopamine hypothesis

Snyder et al

Answer 19

Snyder et al –

Assessed the degree to which various antipsychotic drugs could bind to dopamine receptors.

Added radioactively labelled dopamine to samples of dopamine-receptor-rich neural membranes from calf brains, then rinsed the samples and measured radioactivity to measure the amount of dopamine receptor molecules.

They then looked at the drugs ability to block these receptors, the assumption being that drugs with a high affinity for dopamine receptors would leave less sites blank for dopamine to bind to.

Found that chlorpromazine and other effective antipsychotic drugs had a higher affinity for the dopamine receptor sites than ineffective drugs.

HOWEVER, there were some exceptions, such as haloperidol. Haloperidol is a potent anti-schizophrenic drug, yet displayed a low affinity for dopamine receptors…???

Question 20

4: The dopamine hypothesis

Different kinds of dopamine receptors

Answer 20

Snyder et al’s work led to the discovery that there was more than one type of DA receptor: D1 and D2

Dopamine binds to more than one kind of receptor – explaining why haloperidol seemed to exhibit a low affinity yet was still so potent. 5 receptor subtypes have been classified.

Turns out that chlorpromazine and other anti-schizophrenic drugs in the same chemical class (phenothiazines) all bind to both D1 and D2 receptors, whereas haloperidol and other anti-schizophrenic drugs in the same chemical class (butyrophenones) all bind to D2 but not to D1 receptors.

Revision of the DA theory: Schizophrenia is caused by hyperactivity specifically at D2 receptors, rather than at dopamine receptors in general.

Snyder et al then went on to confirm that the degree to which neuroleptics (anti-schizophrenic drugs) bind to D2 receptors is highly correlated with their effectiveness in suppressing symptoms.

Question 21

What is a neuroleptic?

Answer 21

anti-schizophrenic drug

Question 22

4: The dopamine hypothesis

What is the D2 receptor theory of schizophrenia missing? What can’t it explain?

(4 issues)

Answer 22

The D2 version of the dopamine theory of schizophrenia cannot explain several key experimental findings.

There are 4 key discoveries about schizophrenia that cannot be resolved by a strict interpretation of the D2 version of the dopamine theory – key to the current view that although overactivity at D2 receptors plays a major role in schizophrenia, other factors are yet to be identified.

1. Receptors other than D2 are involved in schizophrenia
2. It takes several weeks of neuroleptic therapy to alleviate schizophrenia symptoms
3. Schizophrenia is associated with widespread brain damage
4. Neuroleptics are only marginally effective

Question 23

4: The dopamine hypothesis

What is the D2 receptor theory of schizophrenia missing? What can’t it explain?

1. Receptors other than D2 are involved in schizophrenia

Answer 23

Recent research has implicated neurotransmitters other than dopamine in schizophrenia, including glutamate and serotonin.

Evidence comes from the development of atypical neuroleptics (those that are not primarily D2 receptor blockers), like clozapine, which has an affinity for D1 & D4 receptors and several serotonin receptors – but only a slight affinity for D2 receptors.

Clozapine is effective in treating patients who have not responded to typical neuroleptics (drugs that primarily act as D2 receptor blockers) and does not produce parkinsonian side effects.
- However, the therapeutic utility of clozapine is limited as it produces a severe blood disorder in some people who use it.

The discovery of atypical neuroleptics led to the qualification of the D2 theory rather than its abandonment for a few reasons…

• Atypical neuroleptics still bind to D2 receptors, just very weakly
• Some evidence supporting the D2 theory doesn’t rest on the assumption that the strength of the binding of drugs to the receptors directly relates to the efficacy of the drug… for example, recently diagnosed schizophrenics who haven’t yet taken neuroleptics can still report having more D2 receptors and more extracellular dopamine than non-schizophrenics

Question 24

4: The dopamine hypothesis

What is the D2 receptor theory of schizophrenia missing? What can’t it explain?

2. It takes several weeks of neuroleptic therapy to alleviate schizophrenia symptoms

Answer 24

This is problematic for the dopamine theory because…

Neuroleptics effectively block activity at the D2 receptors within a matter of hours. The time lag indicates that the blockage of D2 receptors it’s the mechanism that directly produces the drugs therapeutic effect, alleviative symptoms.

Appears that blocking D2 receptors triggers some slow-developing compensatory change in the brain that then directly produces the therapeutic effect.

Question 25

4: The dopamine hypothesis

What is the D2 receptor theory of schizophrenia missing? What can’t it explain?

3. Schizophrenia is associated with widespread brain damage

Answer 25

There have been reports of brain pathology in schizophrenics.

Originally, the reports included descriptions of enlarged cerebral ventricles (where cerebrospinal fluid is produced) - indicating reduced brain size.

Subsequent studies focused on specific cortical areas and subcortical structures. Recent meta-analysis reported reduced volume in 50 different brain regions. Reductions in the number of neurons in many areas & anomalies in neuron structure and circuitry.

This is problematic for the dopamine theory because…

• Little evidence of specific structural damage to the dopaminergic circuits
• Dopamine theory provides no rationale for the diffuse pattern of brain damage that is often observed

Do the brains of schizophrenics develop abnormally, or do they develop normally then suffer damage???

• Substantial damage has been found to already exist in first-episode schizophrenics
• Development of damage to different areas of the brain does not follow the same time course in all patients

Question 26

4: The dopamine hypothesis

What is the D2 receptor theory of schizophrenia missing? What can’t it explain?

4. Neuroleptics are only marginally effective

Answer 26

The main problem with both typical and atypical neuroleptics is that they help only a fraction of schizophrenics. When compared, the effectiveness of chlorpromazine compared to a placebo showed that the beneficial effects of chlorpromazine in under 6 months was surprisingly weak, over six months there were clear benefits but even then, only 1 in 7 patients was helped substantially.

The effectiveness of neuroleptics is limited as most patients stop taking them due to the side effects. Typical neuroleptics produce Parkinson’s-like symptoms. Atypical neuroleptics have their own array of side effects – diabetes, weight gain, problems with fat regulation. Patients are just as likely to stop taking atypical neuroleptics, overall drop-out rate is 74%.

This is problematic for the dopamine theory because…
- Most neuroleptics act on only some symptoms of schizophrenia, which contradicts the dopamine theory which would predict that the drugs should improve the entire condition.

Neuroleptics are more effective in treating positive schizophrenia symptoms (e.g. incoherence, cognitive deficits and delusions) – which are assumed to arise from an increase in neural activity.

Neuroleptics don’t work so well at treating negative schizophrenic symptoms (e.g. lack of affect, cognitive deficits and poverty of speech) – which are assumed to be caused by brain damage.

Atypical neuroleptics are said to be more effective in treating negative symptoms, but any difference between the drug types may be attributed to the lack of parkinsonian side effects.