Schizophrenia and its treatment

Question 1

Psychoses symptoms

Answer 1

Positive symptoms

• delusions (paranoid)
• hallucinations (auditory)
• incoherence
• catatonic or hyperactive behaviour

Negative symptoms (withdrawing)

• flat affect
• Cognitive deficits (attention and memory)
• 50% may attempt suicide, 10% of which are successful.
• Psychotic episodes can occur for hours, days, or long term (months, years).

Question 2

Schizophrenia

Answer 2

About 1% of the population, regardless of social class, culture, education or race, suffer from schizophrenia at some point in their lives.

Schizophrenia affects people in their youth (teens through mid-life, then decreases with age)

Contributing factors include: drug addiction,
alcoholism,
extreme depression,
physical brain damage, overdose of medication, and genetic predisposition.

Schizophrenia ranks among the top 10 causes of disability in developed countries.

Question 3

Long term prognosis

Answer 3

Ten and thirty years after diagnosis of schizophrenia:
25%
25 -35% 15-25% 10-15% 10-15%
Completely Recover
Much Improved, relatively independent Improved, but require extensive support Hospitalized, unimproved
Dead (Mostly Suicide)

Question 4

Is there evidence of a genetic component of schizophrenia?

Answer 4

Yes.
100+ potential susceptibility genes known; so very complex!
These are involved in neuronal development, glutamatergic function and synaptic connectivity.

Risks increase with multiple affected family members.

Question 5

The brain in schizophrenia: Basal Ganglia

Answer 5

Basal Ganglia
- Involved in movement and emotions and in integrating sensory information. Abnormal functioning in schizophrenia is thought to contribute to paranoia and hallucinations (excessive blockade of dopamine receptors in the basal ganglia by traditional antipsychotic medication leads to motor side effects.

Question 6

The brain in schizophrenia: Frontal lobe

Answer 6

Frontal lobe
- critical to problem solving, insight and other high-level reasoning. Pertubations in schizophrenia lead to difficulty in planning actions and organising thoughts.

Question 7

The brain in schizophrenia: Auditory system

Answer 7

Auditory system
- Enables humans to hear and understand speech. In schizophrenia, overactivity of the speech area (Wernickes area) can create auditory hallucinations - the illusion that internally generated thoughts are real voices coming from the outside.

Question 8

The brain in schizophrenia: Limbic System

Answer 8

Limbic System

Involved in emotion. Disturbances are thought to contribute to the agitation frequently seen in schizophrenia

Question 9

The brain in schizophrenia: Hippocampus

Answer 9

Hippocampus

Mediates learning and memory formation, intertwines functions that are impaired in schizophrenia

Question 10

The brain in schizophrenia: Occipital Lobe

Answer 10

Occipital lobe
Processes information about the visual world. People with schizophrenia rarely have full-blown visual hallucinations, but disturbances in this area contribute to such difficulties as interpreting complex images, and recognising motion and reading emotions on others faces.

Question 11

Postulated neuronal dysfunction in schizophrenia: Mesolimbic pathway

Answer 11

Increased activity in this pathway can cause hallucinations, delusions and other positive symptoms.

Overactivity = positive symptoms

Question 12

Postulated neuronal dysfunction in schizophrenia: mesocortical pathway

Answer 12

Decreased activity in the pathway can cause apathy, withdrawal, lack of motivation and pleasure and other negative symptoms.

Dysfunction = negative/cognitive

Question 13

Dopamine Hypothesis of Positive Symptoms of

Schizophrenia

Answer 13

• Repeated administration of stimulants, like amphetamines cocaine, and levodopa which increase DA activity, can cause psychosis that resembles positive symptoms of schizophrenia.
• Low doses of amphetamine can induce a psychotic reaction in schizophrenics in remission.

• Postsynaptic DA receptor antagonism is the common mechanism that explains antipsychotic properties pertaining
to positive symptoms; typical antipsychotic medications generally block D2 receptors.

Question 14

Dopamine receptors

Answer 14

D2 receptors are the most predominant subtype in the brain:
Regulate mood, emotional stability in the limbic system
and movement control
in the basal ganglia.

Question 15

Limitations of the Dopamine Hypothesis of Schizophrenia

Answer 15

• NMDA receptor antagonists worsen cognitive, positive and negative symptoms in unmedicated schizophrenic patients; NMDA agonists may improve symptoms.
• NMDA receptor “hypofunction” may reduce the level of activity of mesocortical DA neurons, reducing activity in frontal cortex.
• There may be decreased levels of glutamate in CSF, prefrontal cortex and hippocampus of schizophrenics.
• Atypical antipsychotics have low affinity for D2 receptors, but are good antagonists of 5-HT2 receptors
• There are wide-spread and complex changes in the 5-HT system in schizophrenics, suggesting involvement of 5-HT.
• Dopamine based antipsychotics are only partially effective in most (70%) and ineffective entirely for some patients.
• Thus, glutamate and serotonin systems may also be involved.

Question 16

Antipsychotic drugs fall into two general categories:

Answer 16

• Older “typical” FGA drugs, pre-1990s, modelled on D2 receptor antagonism; EPS and TD.
• Newer “atypical” SGA drugs, modelled on 5-HT2/D2 receptor antagonism; Fewer EPS; but weight gain, sedation and diabetes increase.
• These drugs are not a cure, and given the disease profile for many, schizophrenics must be treated with medications indefinitely, as the disease is lifelong.

Non-compliance is the major reason and cause for relapse.

Question 17

First “typicals”: Chlorpromazine and other

phenothiazine-type drugs

Answer 17

• First medication to treat schizophrenia. It was unique in that it did not excessively sedate patients, which had been the traditional treatment.
• Hallucinations and delusions often diminish over several days, while other symptoms require weeks for improvement.
• Chlorpromazine is an antagonist for D2 receptors, but also for muscarinic M1, histamine (H1), 5- HT, and alpha-1 adrenergic receptors.

Question 18

ExtraPyramidal Symptoms (EPS)

Answer 18

Blocking of D2 receptors in striatum can lead to Parkinson’s Disease-like.

• Acute dystonia (severe muscle spasms in back, neck, tongue, and face)
• “Parkinsonism” (with shuffling gait, tremor at rest, muscle rigidity, stooped posture);
• Akathisia (inability to rest or relax, always in motion, has trouble sitting still and/or sleeping)
• Tardive dyskinesia (TD) can occur with long-term use (repetitive, involuntary movements of face, arms/legs).
• EPS occurs in about 40-50% of patients given classic antipsychotics.

5-HT2A receptors in the substantia nigra pathway control DA release; block leads to enhanced dopamine release, which may ease EPS.

Question 19

Second line of “typical” attack: Haloperidol and other butyrophenones (non-phenothiazine compounds)

Answer 19

• 50x more potent than chlorpromazine for D2 receptors, with the same efficacy in relief of symptoms.
• Unfortunately, the tendency towards EPS is still high.
• Haloperidol is also used to control the involuntary tics and vocalizations of Tourette’s syndrome (and possible use in Huntington’s Disease).

The antagonism of D2»>D1 receptors in the mesolimbic area of the brain reduces positive psychotic symptoms, with 80% block needed for medicinal effects. Haloperidol is non-selective and also binds and blocks 5-HT2A, histamine H1 and α- adrenergic receptors in the brain.

Question 20

Neurochemistry in schizophrenia

Answer 20

• Hyperactivity of DA transmission is responsible for positive symptoms but this does not mean elevated DA levels;
• The potency of antipsychotic drugs in binding to the D2 receptor family is proportional to the potency of the drugs in treating schizophrenia.

Question 21

Atypical antipsychotic medications: 5-HT2a/D2 theory

Answer 21

• Atypical compounds have increased selectivity compared to the older ‘typical’ neuroleptics, with reduced EPS side effects at therapeutic doses.
• This may be largely due to a decrease in the time frame of receptor occupation.
• FGA bind tightly; SGA bind more loosely for a shorter time frame.

Question 22

“Atypical” clozapine

“Serotonin – dopamine antagonists”

Answer 22

Clozapine treats both positive and negative symptoms; at therapeutic doses, no EPS thus making it atypical, thought to bind to D2 receptors at therapeutic doses with rapid dissociation.
Some SGA’s, including clozapine has 5-HT1A autoreceptor agonism as well, which could increase the dopamine release in the prefrontal cortex and reduce glutamate release.
However, muscarinic ACh, a-adrenergic, 5-HT2a, and H1 (drowsiness) receptors in the brain are blocked. Some patients report weight gain, osteoporosis, and even a tendency towards diabetes Type 2.
Agranulocytosis, however, caused deaths in a number of patients, resulting in clozapine being pulled from the market, but its use in nonresponsive patients led to its return, with the condition that patients on clozapine are required to regularly submit for hematological monitoring to detect granulocytopenia (low conc. of granulocytes, which lower resistance to infection) before agranulocytosis develops.

Question 23

“Atypical” Risperidone

Answer 23

• At therapeutic doses, risperidone antagonises 5-HT2a, D2, and α-adrenoreceptors in the brain;
• and it lacks anticholinergic side effects (no blurred vision, dry mouth) as it is non-mAChR binding. It also has low affinity for D1 receptors.
• Adverse effects associated with atypical antipsychotics, such as tachycardia, impotence and dizziness, are due to the non-selective binding to α-adrenoreceptors, and these affect patient compliance.

Preference of D2»>D1 at therapeutic doses, no block of H1 or ACh receptors.
Risperidone can cause EPS side-effects at high doses, due to loss of receptor binding specificity.

Question 24

Side effects of atypical antipsychotic drugs

Answer 24

Cataracts
Weight gain 
Diabetes (type 2)
Prolongation QTC  Interval 
Myocarditis (inflammation of heart muscle)
Hyperlipidemia 
Sexual side effects
Extrapyramidal symptoms - movement disorders

Question 25

dopamine system stabilisers (DSSs), aripiprazole

Answer 25

Patients less likely to develop EPS

• Mechanism: partial agonist at D2 receptor, which modulates dopaminergic activity in mesolimbic and mesocortical areas of the brain.
• Partial agonist for serotonergic (5-HT1A) receptors,
• Antagonist for serotonergic (5-HT2A) receptors,
• Antagonist to histamine and a-adrenergic receptors
• Has no affinity for cholinergic muscarinic receptors.
• Time will tell if this is an effective long-term treatment for schizophrenia.

Question 26

Antipsychotic comparison

Answer 26

Fewer EPS side effects with atypical antipsychotics, and greater efficacy in treatment-resistant patients and against negative symptoms than with typical antipsychotics;
Some of the newer atypical agents are highly selective for D2 receptors, and the speed of binding and dissociation may be of key importance.
And all antipsychotics interact with multiple targets in the neuronal receptor family, including muscarinic acetylcholine receptors, histamine receptors, adrenergic receptors and serotonin receptors, which may relate to side effects.