Lecture 40: Schizophrenia & Depression

Question 1

What are the 2 different types of symptoms of schizophrenia?

+ give examples of these

Answer 1

1. Positive (above normal) = delusions, auditory hallucinations
2. Negative (below normal) = withdrawal, flattened mood

Question 2

Explain how Dopamine Abnormality has been hypothesized in Schizophrenia

Answer 2

Hypothesis: “Schizophrenic symptoms are due to overactivity of dopamine systems in the mesolimbic/cortical system”.

Substantia nigra compacta (Parkinson’s) - red

• Caudate-putamen (movement control of Parkinson’s)

Ventral tegmental area (schizophrenia) -green

• Frontal cortex
• Nucleus accumbens
• Olfactory areas
• Ventral striatum (limb function)

Evidence

1. Amphetamine = ­ dopamine release

• Induces “paranoid psychosis”
• Exacerbates schizophrenia symptoms
• These 2 symptoms are blocked by DA antagonists

1. All known antipsychotic drugs block dopamine receptors and this correlates highly with clinical efficacy.

Question 3

Explain how Glutamate may be associated with Schizophrenia

Answer 3

Reduction in glutamate system generates schizophrenia symptoms

Evidence

Phencyclidine (PCP/Angle Dust)

• Best model of psychosis, m_odels both positive & negative symptoms_.
• (Better than amphetamine, which only models positive symptoms.)

PCP is a non-competitive antagonist of NMDA subtype glutamate receptor.

Question 4

What are some biochemical theories surrounding schizophrenia?

Answer 4

1) Overactivity of dopamine systems
2) Underactivity of Glutamate systems
3) IncreasedDA + Decreasedglutamate & others (NMDA) -> schizophrenia symptoms

Clinical trials have demonstrated that agonists at the glycine site on NMDA receptor improved negative symptoms of schizophrenia when added to patient’s conventional neuroleptic medication.

Question 5

Describe Neuroleptic Drugs

Answer 5

Neuroleptic Drugs/Anti Psychotics

Require 2-3 weeks of chronic use to obtain Full therapeutic effect.

1. Typical
2. Chlorpromazine (phenothiazine) – tricyclic, related to tricyclic antidepressants, revolutionised psychiatry
   * Dopamine antagonist, antimuscarinic side effects (e.g. xerostomia/dry mouth, - drying up secretions).
3. Haloperidol
   * Dopamine antagonist
4. Atypical
5. Clozapine – resurgence of use, side effects include agranulocytosis (white blood cell disorder characterized by a decreased number of circulating neutrophils).

First-line treatments (Prof. Rob Kydd) would be risperidone & olanzepine first-up, aripiprazole & quetiapine sometimes, followed by clozapine.

Question 6

What are some typical anti-psychotics?

Answer 6

Typical

• Chlorpromazine (phenothiazine) – tricyclic, related to tricyclic antidepressants, revolutionised psychiatry
  
  • Dopamine antagonist, antimuscarinic side effects (e.g. xerostomia/dry mouth, - drying up secretions)..
• Haloperidol
  
  • Dopamine antagonist

Question 7

_______________ mainly work on positive symptoms of schizophrenia.

Answer 7

Chlorpromazine & haloperidol (typical) mainly work on positive symptoms.

Question 8

____________also effective against negative symptoms (as well as positive).

Answer 8

Clozapine (atypical) also effective against negative symptoms (as well as positive) in Schizophrenia

Question 9

What is another name for anti-psychotics?

Answer 9

Neuroleptic Drugs

Question 10

Describe the Mechanism of Action of the Anti-psychotic drugs

Answer 10

1. Site of Action

All dopamine receptor (D1-D5) antagonists

• Haloperidol & chlorpromazine have equal affinity for D2 and D4 receptors.
• Clozapine has 10-fold greater affinity for D4 than D2 receptors.

D1 receptors -> Increased cAMP (High in striatum)

D5 is similar to D1

D2 receptors -> Decreased cAMP (High in Striatum)

D3 = D2-like but (High in Limbic system)

D4 = D2-like but (High in cortex and Limbic system) and (low in striatum)

1. Mechanism of Action

Haloperidol & chlorpromazine (“typical”) show extrapyramidal side effects (EPSs) such as tardive dyskinesia’s (oro-facial movements) and “Parkinsonian” symptoms.

Perhaps EPSs caused by block of D2 receptors in striatum (extrapyramidal motor system) (nigrostriatal DA pathway)

Clozapine does not cause EPSs perhaps due to low D2 affinity.

Theories:

1) Perhaps therapeutic effects caused by block of D4/D3 receptors in limbic system/cortex (mesolimbic/cortical DA pathway)?
2) Another view is that D2 receptors in cerebral cortex mediate antipsychotic effects, and D2 receptors in striatum mediate extrapyramidal side effects of neuroleptics. This is based upon studies of chronic neuroleptic administration (upregulation when antagonized is a biomarker for drug action) showing that D2 receptors are upregulated only in cortex with clozapine, but in cortex and striatum with haloperidol.

Inferred that clozapine is working at D2 on the cortex

Question 11

Where are the different dopamine receptors found?

Answer 11

D1 receptors -> Increased cAMP (High in striatum)

D5 is similar to D1

D2 receptors -> Decreased cAMP (High in Striatum)

D3 = D2-like but (High in Limbic system)

D4 = D2-like but (High in cortex and Limbic system) and (low in striatum)

Question 12

Haloperidol & chlorpromazine (“typical”) show extrapyramidal side effects (EPSs) such as tardive dyskinesia’s (oro-facial movements) and “Parkinsonian” symptoms.

What might be the cause of these symptoms?

Answer 12

Blocking of D2 receptors in the striatum

Perhaps EPSs caused by block of D2 receptors in striatum (extrapyramidal motor system) (nigrostriatal DA pathway)

Clozapine does not cause EPSs perhaps due to low D2 affinity.

Question 13

Define Depression

Answer 13

Depression is an episodic, recurrent illness with periods of spontaneous remission

Question 14

What are the 2 types of Mood disorders?

Answer 14

1. Unipolar depression = mood, appetite, tiredness, negative self-concept.

• Endogenous depression = unknown origin;
• Reactive depression = associated with environmental event.

1. Bipolar (m__an__i__c) depression

• Strong genetic basis;
• Mood fluctuates 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 (called manic-depressive psychosis)

Question 15

Monoamine neurotransmitters such as noradrenaline, serotonin, and dopamine are inactivated by two main mechanisms……………………

Answer 15

Monoamine neurotransmitters such as noradrenaline, serotonin, and dopamine are inactivated by two main mechanisms:

1. Reuptake into the neuron;
2. Breakdown by monoamine oxidases (MAOa and MAOb). MAOa breaks down noradrenaline and serotonin; MAOb breaks down dopamine. Catechol-O-methyl-transferase (COMT) also degrades monoamines.

Antidepressant drugs work acutely by either of the above two systems (reuptake; breakdown).

Question 16

What are the problems with the idea that depression is caused by decreased monoamine activity? (Simple monoamine theory)

Answer 16

Although antidepressants produce an immediate increase in monoamine levels (noradrenaline and serotonin) in the brain, the therapeutic action of these drugs is delayed and only becomes apparent 2-6 weeks after chronic use. (if the monoamine theory was correct, why is there a delay?)

Therefore, perhaps the therapeutic effect of antidepressant drugs results from a change in brain chemistry/function after chronic use (long-term adaptive changes).

Question 17

What are the first generation antidepressant drugs?

Answer 17

1. First Generation
2. Tricyclics – amitriptyline, imipramine

• Acute effects = block of noradrenaline and serotonin reuptake
• Chronic effects = ??? ¯β1‐adrenoceptors
• Side effects = antimuscarinic actions (reduce secretions)
• Benefit 75% of patients (cf. placebo response = 30-40%)?

1. MAO (monoamine oxidase) inhibitors – phenelzine (mostly replaced)
   * Irreversibly inhibits MAO’s and i_ncreases levels of noradrenaline, serotonin and dopamine_

Question 18

Name 2 tricyclics

Answer 18

First generation drugs

amitriptyline, imipramine

• Acute effects = block of noradrenaline and serotonin reuptake
• Chronic effects = ??? ¯β1‐adrenoceptors
• Side effects = antimuscarinic actions (reduce secretions)
• Benefit 75% of patients (cf. placebo response = 30-40%)?

Question 19

Name a MAO inhibitor

Answer 19

(Monoamine oxidase inhibitors)

e.g. phenelzine

(mostly replaced)

• Irreversibly inhibits MAO’s and increases levels of noradrenaline, serotonin and dopamine

Question 20

What are the Second generation antidepressants?

Answer 20

Lots, but a few are listed below

1. Moclobemide – reversible MAOa selective inhibitor which produces acute increase in noradrenaline and serotonin
2. Fluoxetine (Prozac) – potent, selective serotonin reuptake inhibitor (SSRI)

• Its use has shifted depression research to the serotonin area;
• It’s better tolerated than tricyclic antidepressants (TCAs), depends on individuals.

1. Paroxetine (aropax) and citalopram also widely used.

Question 21

What are 2 treatment drugs for Manic Depression

Answer 21

Lithium carbonate is the most effective treatment on manic depression, no effect on unipolar depression.

• 3 weeks onset of action latency;
• Stabilizes both manic and depressive phases;
• Overdose results in tremor, seizures, coma, death (low therapeutic index).
• Mechanism = dampening of phosphoinositide-mediated neurotransmission may explain its normalizing effects in treating both mania and depression.

Carbamazepine & sodium valproate (anti-convulsants) are also used in manic depression especially for rapid (4-5 cycles/year) cyclers

Question 22

Describe the links between depression and neurogenesis

Answer 22

A study (Lancet 356, 1241, 2000) found using MRI that lithium treatment of patients with manic depression increased grey matter volume. Also, studies have shown that lithium stimulates neurogenesis in the brain. Other antidepressants (e.g. fluoxetine) can also p_romote neurogenesis_. Stress can reduce neurogenesis.

These studies suggest that impaired neurogenesis may play a role in depression and anti-depressant drugs may act to promote endogenous neurogenesis. Lithium is also neuroprotective (esp. after chronic treatment suggesting that this may also somehow be involved in its MOA?).