Lecture 40: Schizophrenia and depression -treatment

Question 1

Schizophrenia is? Symptoms described as? Onset?

Answer 1

Disorder of abnormal thought, perception, behavior, mood and attention

Symptoms are:

• positive = delusions, auditory hallucinations (above what is described as normal)
• negative = Withdrawal, flattened mood (below what is normal)
• Onset is usually between 15-35 y/o and effects 1% of popuation

Question 2

Biohemical theory 1? evidence for this?

Answer 2

Dopamine - Schizophrenic symptoms are due to overactivity of dompamine systems in the medolimbic/cortical systems -

• Evidence: Amphetamines cause dopamine release causing paranoid psychosis, exacerbations of existing schiz and are blocked by DA antaganists
• All known antipsychotic drugs block dopamine receptors and the corrolated highly with clinical efficacy.

Question 3

Biohemical theory 2? evidence for this?

Answer 3

2. Glutamate - decreased glutamate systems = schiz symptoms

• phencyclidine (PCP, angel dust) = best model of psychosis
• PCP models both positive and negative symptoms by blocking NMDA (a glutamate sub-type) receptor non-compeditively
• It was noted that giving glycine (a co-agonist for NMDA) improved the negative symptoms when added to the patients conventional neuroleptic medication

Question 4

Typical neuroleptic drugs/anti-psychotics?

Answer 4

1. Chlorpromazine (phenothiazine) - tricyclic, related to TC antidepressants = is a dopamine antagonist
   * BUT Side effects are to do with being a antimuscarinic so will dry up secretions
2. Haloperidol - Dopamine antagonist

Both these work on the positive symptoms + Take a few weeks of chronic use before they begin to work

Question 5

Atypical neuroleptic/anti-psychotic drugs?

Answer 5

1. Clozapine - Resurgance of use, side-effects include agranulocytosis (WBC disorder with decresed neutrophils)

Effective against negative symptoms as well as postive

Question 6

First line treatment in the clinic?

Answer 6

1. Risperidone and Olanzepine
2. Aripiprazole and Quetiapine
3. sometimes followed by clozapine

= All dopamine antagonist

Question 7

Mechaism of action + site of action

Answer 7

• All dopamine receptors (D1-D5) antagonists
• D1 and D5 are similar
• D1 is high in the Striatum and increased cAMP
• D2 reduces cAMP (also high in striatum)
• D3, D4 = similar to D2 but high in limbic and frontal cortex

Question 8

Clozapine, Haloperidol and Chlorpromazine affinity for D-recpetors

Answer 8

Clozapine has 10 fold greater affinity for D4 than D2

Haloperidol and Clorpromazine have an equal affinity for D2 and D4 receptors

Question 9

SE of haloperidol and chlorpromazine? Clozapie

Answer 9

These Typical drugs show extrapyramidal side-effects (EPS) such as Tardive dyskinesia’s (oro-facial movements) and parkinsonian symptoms.

Perhaps EPS caused by block of D2 receptors in the Striatum (extrepyramidal motor system) - Nigrostriatal DA pathway.

Clozapine does not cause EPS due to low D2 affinity

Question 10

Ideas on where the therapeutic effects come from?

Answer 10

• Perhaps due to blocking D4/D3 receptors in the limbic system/cortex (mesolimbic/cortical DA pathway)
• Or maybe that D2 receptors in the cerebral cortex mediate the antipsychotic effects and those in the striatum the EPS.

Question 11

Depression defiinition

Answer 11

Is an episodic, recurrent illness with periods of spontaeous remission. 2% pop affected. Affective = mood disorders

Question 12

Main types of depression?

Answer 12

1. Unipolar - dpreseed mood, apetite, tiredness, negative self-conception = Endogenous (unknown origin) or Reactive (associated with env event)
2. Bipolar - Manic depression = strong genetic basis, mood fluctuations between depression and mania

Mania = heightened mood/euphoria, irritability, poor insight into the consequences of sudden irrational decisions and in severe cases delusions and hallucinations (manic-depressive psychosis)

Question 13

Biochemical theories for depression? evidence?

Answer 13

Simple monoamine theory = as a result of a decrease in brain monoamines (NA, 5-HT, Dopamine)

evidence:

• reserpine - depletes monoamine stores causes depression in some people
• amphetamine/cocaine which raise monoamine levels increase mood
• Antidepressants produce acute increase in brain monoamines by blocking re-uptake or metabolism

Question 14

Inactivation of monoamines?

Answer 14

1. Re-uptake into the neuron
2. Monoamine oxidase (MAOa - NA and 5-HT) (MAOb - Dopamine)
3. COMT also degrades monoamines

Anti-depressants all work acutely by blocking the action of these^^

Question 15

How long does it take to begin to feel better?

Answer 15

Raising the monoamines is likely to be part of the mechanism but must be raised for 2-6 weeks before there is a therapeutic benefit.

Thought that it may be due to a change in brain chemistry/fuction after chronic use (lont-term adaptive changes)

Question 16

Anti-depressant drugs? 1st gen

Answer 16

1. Tricyclics - Amitriptyline, imipramine

• ​Acute effects = Block NA and 5-HT reuptake
• unknown chronic effects (there is dec. Beta 1-adenoreceptors)
• antimuscarinic actions
• benefit 75% of patients (where placebo response is 30-40%)

2. MAO (monoamine oxidase) - inhibitors = Phenelzine
   * irreversibly inhibits MAO and increases monoamines

Question 17

Anti-depressants (2nd gen)?

Answer 17

1. Moclobemide - reversible MOAa inhibitor =(dec NA 5-HT)
2. Fluoxetine (prozac) - SSRI (better tolerated than TCA’s)
3. Paroxetine and citalopram also widely used

Raise serotonin but require chronic use

Question 18

Manic Depression treatment?

Answer 18

Lithium Carbonate

• 2-3 week onset of action latency
• no effect on unipolar dpression
• stabilizes bpth the manic and depressive phases
• OD- tremor, seizures, coma, death

Dampening of phosphoinositide-mediated neurotransmission may explain its normalizing effect. = Stimulates neurogenesis

Carbamazapine and sodium valproate are used in manic depression esp in rapid cyclers.