Antipsychotics

Question 1

What are antipsychotics used for?

Answer 1

They are primarily used in the treatment of schizophrenia, but are also indicated in other disorders – bipolar, agitation, psychosis, Touette’s, etc.

Question 2

What is an additional indication for the second generation antipsychotics?

Answer 2

Mood stabilization; they may also be used as an adjunct in refractory depression or anxiety.

Question 3

All antipsychotics (first and second generation) work via this mechanism:

Answer 3

All antipsychotics block D2 dopamine receptors.

Question 4

What are the four dopamine pathways?

Answer 4

(1) Nigro-striatal; (2) mesolimbic; (3) mesocortical; and (4) tuberoinfundibular.

Question 5

Describe the nigro-striatal pathway:

Answer 5

Dopamine here acts as an inhibitory neurotransmitter in the extra-pyramidal system; it filters extraneous stimuli to allow fine motor movements.

Question 6

Describe the mesolimbic pathway:

Answer 6

This pathway communicates with the amygdala and hypothalamus to process sensory stimuli.

Question 7

Describe the mesocortical pathway:

Answer 7

This pathway branches into the cerebral cortex; dopamine here is responsible for the learning response, attention, decreasing distractibility, and for the awakening response.

Question 8

Describe the tuberoinfundibular pathway:

Answer 8

This pathway communicates to the pituitary gland; dopamine here acts as an inhibitory neurotransmitter to inhibit/diminish the secretion of prolactin.

Question 9

What is schizophrenia?

Answer 9

A disorder characterized by two types of symptoms – positive symptoms (hallucinations, delusions, paranoia); and negative symptoms (apathy, anhedonia, etc.)

Question 10

What causes the positive symptoms of schizophrenia?

Answer 10

Hyper-dopaminergic activity in the mesolimbic system (improper processing of sensory stimuli).

Question 11

What causes the negative symptoms of schizophrenia?

Answer 11

Hypo-dopaminergic activity in the mesocortical system (these symptoms are progressive).

Question 12

Describe why the first-generation antipsychotics treat the positive symptoms while worsening the negative symptoms:

Answer 12

These drugs indiscriminately block dopamine in both the mesolimbic system and the mesocortical system.

Question 13

Describe the relationship between dopamine and serotonin:

Answer 13

They have an inverse relationship; the second generation antipsychotics take advantage of this fact to treat both the positive and negative symptoms of schizophrenia.

Question 14

How do the second generation antipsychotics work?

Answer 14

They block dopamine receptors in the mesolimbic system to treat the positive symptoms; they block serotonin receptors in the mesocortical system to selectively increase dopamine here and treat the negative symptoms.

Question 15

Why does blocking serotonin receptors have no effect on dopamine levels in the mesolimbic system?

Answer 15

Because there are no serotonin receptors; there are only serotonin receptors in the mesocortical system.

Question 16

What are the effects of dopamine blockade in the nigro-striatal pathway?

Answer 16

Dopamine blockade here can precipitate Parkinsonian effects; however, the inverse relationship between dopamine and serotonin exists here as well.

Question 17

Why do the second generation antipsychotics have fewer Parkinsonian side-effects than the first-generation antipsychotics?

Answer 17

Because they block serotonin in the nigro-striatal pathway in order to prevent loss of dopamine here.

Question 18

What is the relationship between dopamine and ACh?

Answer 18

This is also an inverse relationship (although the effect is not as robust).

Question 19

Describe the efficacy of the second generation antipsychotics:

Answer 19

They are relatively weak dopamine blockers; while a low dose can provide effective mood stabilization, a much higher dose would be needed to treat hallucinations.

Question 20

What causes the wide range of ADRs seen with antipsychotics?

Answer 20

These drugs block other receptors as well – histamine receptors; acetylcholine receptors; and alpha-1 receptors.

Question 21

What ADRs occur as a result of histamine-receptor blockade?

Answer 21

Sedation and weight gain.

Question 22

What ADRs occur as a result of acetylcholine receptor blockade?

Answer 22

Anticholinergic ADRs – dry mouth, blurred vision, tachycardia.

Question 23

What ADR occurs as a result of alpha-1 blockade?

Answer 23

Orthostatic hypotension.

Question 24

What ADRs occur as a result of serotonin receptor blockade?

Answer 24

Weight gain; carbohydrate craving.

Question 25

What ADRs occur as a result of D2 dopamine receptor blockade?

Answer 25

Parkinsonian effects (reversible); akathesia; tardive dyskinesia (irreversible; caused by EPS blockade); acute dystonia; impotence; and galactorrhea.

Question 26

What is tardive dyskinesia?

Answer 26

An irreversible ADR seen in those on long-term therapy; caused by prolonged D2 blockade in the nigro-striatal blockade, and upregulation of dopamine receptors; involves involuntary facial, lingual, limb movements.

Question 27

What are the two first-generation antipsychotics currently in use?

Answer 27

Thrazine (chlorpromazine) – low potency; and Haldol (haliperidol) – high potency.

Question 28

What are the second-generation antipsychotics currently in use?

Answer 28

Clozapine; risperidone; olanzapine; quetiapine; ziprasidone; aripiprazole; palpiperidone; iloperidone; asenapine; and lurasidone.

Question 29

What causes the weight gain, cholesterol, and glucose changes seen with antipsychotics?

Answer 29

These changes can be very significant; they are caused by histamine blockade (increased appetite) and decreased insulin sensitivity. Patients must be monitored at baseline, and several times a year.

Question 30

What is another significant ADR of antipsychotics?

Answer 30

Neuroleptic malignant syndrome – rigidity,mfever, leukocytosis, altered cognition, elevated CK); occurs in those sensitive to EPS effects.