Psychopharmacology of Antipsychotics

Question 1

Points to Consider:

Answer 1

• Antipsychotics have some of the most complicated neuropsychiatric interactions and pattern of binding to neurotransmitter receptors
• At least 15 receptors to which antipsychotics bind and only a few are known to have an understood clinical significance but many are clinically relevant (we will discuss only 3‐4 of them)
• Information is likely to change in the next decade, with glutamate likely to be a key neurotransmitter of clinical attention
• Link of receptor binding to clinical action is still a HYPOTHESIS, albeit one with significant evidence to date
• Most data to date focuses on dopamine but other neurotransmitters are also involved

Question 2

First Generation

Answer 2

• LOW POTENCY
• Chlorpromazine
• Thioridazine
• HIGH POTENCY
• Perphenazine
• Fluphenazine
• Haloperiodol
• Pimozide

Question 3

Second Generation

Answer 3

• Clozapine
• Risperidone
• Olanzapine
• Questiapine
• Ziprazidone
• Paliperidone

Question 4

Third Generation

Answer 4

-Aripoprazole

Question 5

First Generation (typicals, “neuroleptics)

Answer 5

• Chloropromazine – first discovered in the 1950s by accident (antihistamine with antipsychotic effects in schizophrenia)
• subsequent antipsychotics discovered through their ability to produce “neurolepsis” in animal models
  
  • Psychomotor slowing, emotional writing, affective indifference
• easy to become enamored of a medication
• ensure that medications are used for relevant symptoms

Question 6

neurolepsis

Answer 6

Psychomotor slowing, emotional quieting, affective indifference

Question 7

agonist

Answer 7

amphetamine promotes the release of dopamine and foster symptoms of Sz
-both amphetamine and cocaine block reuptake of dopamine and foster symptoms of Sz

Question 8

antagonist

Answer 8

chlorpromazine, blocks the symptoms of Sz, occupies the dopamine site on the D2 receptor, preventing receptor activation by dopamine

Question 9

First Generation vs Second Generation Antipsychotics

Answer 9

• By 1970’s, antipsychotic properties were characterized by the ability of neuroleptics to block Dopamine (D2) receptors
• Classification based on potency of binding to D2 receptors, not efficacy of medication (HIGH and LOW potency). Also divided into chemical families.
• Positive symptom reduction (psychosis) due to blockade of D2 receptors in the mesolimbic dopamine pathway
• Side effects of typical antipsychotics due to blockade of D2 receptors throughout the brain, not just in the mesolimbic pathway

Question 10

Nigro-Striatal pathway

Answer 10

movement (EPS, Tardive dyskinsea)

Question 11

Meso-Limbic Pathway

Answer 11

“reward” pathway (positive symptoms of Sz)

Question 12

Meso-Cortical pathway

Answer 12

motivation and emotion (negative symptoms of Sz)

Question 13

Tubulo-infundibular pathway

Answer 13

posterior pituitary (hyperprolactinemia)

Question 14

Side Effects of 1st Generation Antipsychotics by System

-Mesolimbic

Answer 14

(site of nucleus accumbens, “pleasure centre” of the brain and part reward pathway)

• Stimulation -> pleasure
• Blockade -> apathy, anhedonia, a-motivation lack of interest in social interaction (secondary negatives symptoms)

Question 15

Side Effects of 1st Generation Antipsychotics by System

2. Mesocortical Pathway

Answer 15

2a. to Dorsolateral Prefrontal Cortex (DLPFC)
• Secondary Negative Symptoms
• Worsening of cognitive symptoms

2b. To Ventromedial Prefrontal Cortex
(VMPFC)
• Secondary Negative Symptoms
• Worsening of Emotional (Affective) Symptoms

Question 16

3. Nigrostriatal Pathway (EPS and TD) cont.

Answer 16

• TD thought to be due to D2 receptors “up-regulating” and
becoming hypersensitive to dopamine
• 5% of patients per year on conventional antipsychotics develop TD (i.e. 25% by year 5); elderly up to 25% per year develop TD (i.e. “number needed to harm” = 4 every 5 years for young adults and 4 every year for the elderly)
• Those developing EPS early in treatment twice as likely to develop TD
• Risk of onset of TD decreases after 15 years of treatment (likely due to genetic protective factors)

Question 17

4. Tuberoinfundibular Dopamine Pathway

Answer 17

• Projects from the hypothalamus to the pituitary gland
• Unaffected in untreated schizophrenia
• Dopamine D2 blockade elevates plasma PROLACTIN levels (hyperprolactinemia), causing galactorrhea (breast milk secretion) in men and women and amenorrhea (irregular menses) in women

Question 18

-conventional antipsychotics usually block some combo of

Answer 18

(a) alpha-1 adrenergic (b) histamine-1 and (c) muscarinic cholinergic receptors, accounting fir their different side effect profiles

(A) (a) alpha-1 adrenergic - dizziness, drowsiness, postural hypotension

(B) b) histamine- – weight gain, drowsiness

(c) c) muscarinic cholinergic receptors - muscarinic cholinergic side effects – blurred vision, dry mouth, constipation, urinary retention, cognitive dysfunction

• In the nigrostriatal pathway, dopamine inhibits acetylcholine release, so when there is less dopamine, there is more acetylcholine, increasing likelihood of EPS.
• Can block acetylcholine release with “anticholinergic” medications or give antipsychotic medications with anticholinergic effects to lessen EPS (but not reduce likelihood of TD)

Question 19

Second Generation Antipsychotics

-what makes an antipsychotic medication “atypical”?

Answer 19

• originally used to describe lower EPS risk associated with clozapine
  
  • term expanded later to include greater efficacy in trading cognitive and negative symptoms, lack of prolactin elevation, greater efficacy for treatment-resistant patients

Question 20

1. Rapid dissociation from D2 receptors

Answer 20

attaches to D2 but releases much faster than Gen 1. Loosely bound medicine

Question 21

2. Serotonin (5‐hydroxytryptamine, 5‐HT) Dopamine Antagonism

Answer 21

5‐HT(1A) receptors ‐ Increase dopamine

5‐HT(2A) receptors ‐ Decrease dopamine

So…. 5‐HT(2A) antagonist increases dopamine by disinhibiting the dopamine neuron

A. .ReducesEPS–IntheNigrostriatalPathway,atypicalsactasadopamineantagonists,
butalsotheserotoninantagonismstimulatesdopamineproduction,
overcomingtheeffectofdopamineblockade

B. Reduces Negative Symptoms– Increases dopamine release in the prefrontal cortex. D2 receptors are not very dense here so there is little
D2 blockade. When 5HT2A is inhibited, more dopamine is produced, resulting in activation of the mesocortical pathway

C. Improve positive symptoms through action on glutamate

D. Reduce prolactin elevation by blocking excitatory role of serotonin on prolactin production

Question 22

3. Serotonin (5‐hydroxytryptamine, 5‐HT) 1A Partial Agonism

4. D2 Partial Agnoism (actually THIRD GENERATION ANTIPSYCHOTICS) “Goldilocks drugs” – Aripiprazole

Answer 22

• Stabilizes dopamine transmission between antagonism (like typicals) and full stimulation (like dopamine)
• Reduce D2 hyperactivity in mesolimbic dopamine neurons enough to exert antipsychotic effect without completely blocking D2 receptor but also only partially block the nigrostriatal pathway (not enough to cause EPS since a little bit of the signal still gets through

Question 23

side effects of Gen 2

Answer 23

-Cardiometabolic risk

Most common side effect (CATIE Study)

• Hyposomnia/sedation
• common reasons for discontinuation include weight gain, EPSS, sedation
• Clozapine – unique side effect profile and monitoring requirement of frequent (up to weekly) bloodwork or monitor fir agranulocytosis (low white blood cells)
• shortens life by 20-30 years (Sz and medications)

•Orthostatichypotension,QTcprolongation(riskofcardiacarrhythmias) •SeriousbutrareeventsincludeDiabeticKetoacidosisand NeurolepticMalignantSyndrome