L12 Antipsychotic Drugs

Question 1

Learning Outcomes (for general perusal)

Answer 1

1. To understand the mechanism of action of the antipsychotic medications
2. This means you must also understand the “dopamine hypothesis” of schizophrenia
3. Gain a good knowledge of the clinical use of the antipsychotics including awareness of the most common and more serious side-effects of these medications

Question 2

What are the general classifications of psychiatric disorders?

Answer 2

1. Organic Disorders
2. Functional Disorders
3. Personality Disorders

Question 3

What are Functional Disorders?

Answer 3

Disordered function without the gross brain abnormality seen in organic disorders such as dementia

• Psychoses => Psychotic symptoms (connected to mood disorders therefore)
• Mood Disorders
• Anxiety Disorders

Question 4

WHAT ARE PSYCHOTIC SYMPTOMS?

Answer 4

These are symptoms that indicate someone has lost touch with reality.

•Two types: delusions and hallucinations.

Question 5

What are delusions?

Answer 5

fixed, false belief out of keeping with a person’s social, educational and cultural background.

eg. belief that MI5 have bugged your home

Question 6

What are hallucinations?

Answer 6

a sensory perception in the absence of a stimulus in the environment.

Patients also ‘lose insight’ into the fact that anything is wrong.

eg. hearing voices

Question 7

SCHIZOPHRENIA

1. What does this syndrome present with?
2. What is it often accompanied by?
3. What is the setting for this syndrome

Answer 7

1. bizarre delusions, disorder of thought form (the way in which a person expresses themselves is confused and confusing), auditory hallucinations, strange behaviour
2. progressive deterioration in personal, domestic, social and occupational competence.
3. clear consciousness and in the absence of an ‘organic’ cause

Question 8

Schizophrenia

1. What are the two main symptom groups?

Answer 8

1. +ve symptoms (also known as “acute”)-(delusions and hallucinations) - respond to antipsychotics, which are DA receptor antagonists.

-ve symptoms ie something is lost-(eg blunted affect, poverty of speech and loss of drive) - usually chronic and do not respond well to treatment.

Question 9

Risk of Schizophrenia as a function of genetic relatedness

Answer 9

Question 10

Antipsychotics - History

General Perusal

Answer 10

• Prior to 1950s rauwolfia (reserpine) was used in India and elsewhere but was limited by adverse effects and limited effectiveness. Electro-convulsive treatment (ECT) was in use from the 1930s but has limited efficacy and no longer used.
• 1952 Laborit et al noted a calming effect of promethazine (an antihistamine) when researching new drugs for use in anaesthesia.
• Attempts to maximise this effect resulted in the synthesis of chlorpromazine.
• Report of beneficial effects in schizophrenia by Delay & Deniker in Paris (1952).
• Rapidly came into use around world.
• The term ‘neuroleptic’ was coined in 1955 and was initially the common name . Subsequently also called ‘major tranquillisers’.
• The term antipsychotic is now preferred.

During their first decade of use it was not clear how these drugs worked.

• 1963 Carlsson & Lindqvist showed in laboratory animals that all effective antipsychotics induce increased turnover of dopamine (DA).
• 1967 Persson & Roos showed this also occurs in humans.
• 1976 Creese, Burt & Snyder demonstrated a relationship between effects on the DA system and clinical effectiveness.

Question 11

Antipsychotics - Main actions

1. How do they reduce psychotic symptoms?
2. What is the effect independant of?
3. Which schizophrenia symptoms are they most effective on?

Answer 11

1. acting as antagonists at dopamine receptors.
2. any sedative effects, i.e. cannot be reproduced by drugs like benzodiazepines AND any psychomotor slowing or extrapyramidal side-effects of the drugs (e.g. Parkinsonian type effects).
3. The +ve symptoms (acute symptoms) of hallucinations and delusions
   
   1. Unclear of effect on -ve symptoms

Question 12

The Dopamine Hypothesis

1. Why does Schizophrenia result from excess activity of dopamine neurotransmission?
2. Why must it be more complex that this hypothesis?

Answer 12

1.

• ALL antipsychotic drugs block dopamine receptors.
• Stimulant drugs which act through dopamine can produce schizophrenic-like behaviors (eg.amphetamines).
• Levodopa, a dopamine precursor, can exacerbate schizophrenic symptoms, or occasionally elicit them in non-schizophrenic patients.
• Higher levels of dopamine receptors measured in brains of schizophrenics
• Brain dopamine increases during psychotic episodes but not during remissions.

2.

• All antipsychotic drugs which block dopamine receptors do not reverse all symptoms
  
  • positives are more responsive
  • negatives may even be exacerbated
• Antipsychotics blocking DA and 5-HT receptors seem better for both positive and negative symptoms
• DA metabolites in CSF & plasma not significantly elevated in people with schizophrenia
• Antipsychotic drugs block DA receptors immediately but antipsychotic benefits take several days to weeks to occur

Question 13

What are the dopamine pathways?

Answer 13

1. Nigrostriatal
2. Mesolimbic and mesocortical
3. Hypothalamic-pituitary

Question 14

1. What is dopamine synthesized from? Under the action of what?
2. What are the precursors to dopamine?
3. What breaks down dopamine?
4. What break it down after reuptake - what is the products?

Answer 14

1. Tyrosine. Tyrosine Hydroxylase
2. L-Tyrosine and L-Dopa
3. monoamine oxidase (MAO), catechol-O-methyl transferase (COMT)
4. MAO. DOPAC dihydroxy-phenyl-acetic acid

Question 15

In the dopaminergic synapse, what Rs are on the

1. Pre-synaptic membane
2. Post-synpatic membrane

Answer 15

1. D-2 AutoR
2. D-1 Like and D-2 Like

Question 16

When a subject is injected with a labelled ligand for DA receptors, where are the ‘hot areas’ on the PET scan?

What will the PET scan show after treatment with antiP drug?

Answer 16

in the caudate-putamen region where the ligand binds to DA receptors.

Ligand no longer able to bind to receptors because antipsychotic drug is bound to receptors. Less activity seen.

Question 17

What are the dopamine (DA) Receptors?

Which are focused on?

D-1 and D-2

Answer 17

G-Protein Coupled Receptors

D-1 Like: activate cyclic-AMP (linked via Gs)

D-1 : caudate-putamen, Nuc. accumbens, olf tubercle

D-5: hippocampus, hypothalamus

D-2 Like: inhibit c-AMP (linked via Gi)

D-2: caudate-putamen, Nuc. accumbens, olf tubercle

D-3: olf tubercle, hypothalamus, Nuc. accumbens, cerebellum

D-4: frontal cortex, medulla, midbrain

Question 18

Where do AntiPs act as antagonists?

(NT receptors)

What brings about the clinical AntiP effect?

Answer 18

• dopamine
• histamine
• alpha-adrenergic
• muscarinic cholinergic
• serotonergic
  
  • Some have a very broad spectrum of action at receptors while the effects of others are more restricted.

DA receptor antagonism, principally at D2 receptors.

Question 19

What are the ‘Typical Antipsychotics’?

Give ONE example

Answer 19

First Generation (1950s)

• phenothiazines (chlorpromazine, trifluoperazine, fluphenazine)
• thioxanthines (flupenthixol, zuclopenthixol)
• butyrophenones (haloperidol)
• diphenylbutylpiperidines (pimozide)
• substituted benzamides (sulpiride)

phenothiazines (chlorpromazine)

Question 20

What are the ‘Atypical Antipsychotics’?

Give ONE example

Answer 20

Second Generation (1990s)

• amisulpride
• olanzapine
• quetiapine
• resperidone
• sertindole
• ziprasidone
• zotepine

amisulpride

Question 21

How do 2nd generation drugs differ from 1st generation drugs?

(AntiPs)

What are they modelled on?

What is a problem with the drug mentioned above?

Answer 21

–less extra-pyramidal side effects

–higher 5-HT2 / D2 ratio of receptor effects

–less potent at D2 receptors

–may be more effective for ‘negative’ symptoms

clozapine because of it’s particular benefits

1-2% develop agranulocytosis (a deficiency of granulocytes in the blood, causing increased vulnerability to infection.) and 5-10% develop neutropenia

Question 22

What effects are associated with dopamine blockade at

1. Mesolimbic tract
2. Nigrostriatal tract
3. Tuberoinfundibular tract

Answer 22

1. therapeutic effect
2. extrapyramidal side-effects
3. endocrine effects - ↑ prolactin secretion (galactorrhoea = excessive or inappropriate production of milk.)

Question 23

What is responsible for the negative feeback in dopamine release?

Answer 23

D-2 Like Receptor

Question 24

Effect of antipsychotics on DA neurones

1. Antipsychotic drugs are competitive antagonists at the DA receptor. What effect will this initially give?
2. When is this negative feedback restored?

Answer 24

1. PostSRs are blocked, Presynaptic autoR is blocked, less NEGATIVE FEEDBACK, greater dopamine release, more HVA being produced when it is broken down.
2. 2-4 weeks, full antiP effect can now be achieved

Question 25

What are the main side effects of AntiPs?

Answer 25

* **Acute dystonias** - sustained muscle contractions cause twisting and repetitive movements or abnormal postures * **Parkinsonism** * **Akathisia** - A movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. * **Tardive dyskinesia -** a neurological disorder characterized by involuntary movements of the face and jaw.

Question 26

**Acute Dystonias** 1. Who are they more common in? 2. What other drug can they be caused by? 3. When do they occur? 4. What is the classic symptoms? 5. What causes them? 6. How can they be treated?

Answer 26

1. men and young 2. metoclopramide 3. Rapid onset after first few doses or after starting a depot 4. **oculogyric crisis** - can last for several hours if not treated. torsion dystonia and torticollis, spasms of muscles of lips, tongue, face and throat (facial grimacing). Extreme spasms of tongue and throat can cause jaw dislocation 5. Presumably due to **imbalance** between nigrostriatal dopamine and acetylcholine as a result of a drug-induced deficit in dopaminergic function 6. **anticholinergics** (benzhexol, procyclidine-IM, IV, oral)

Question 27

**Tardive Dystonia** 1. What do they involve?

Answer 27

1. Retrocollis or torticollis, Trunk/extremeties, Pisa syndrome, Difficult to treat 2.

Question 28

**Pseudo-Parkinsonism** 1. What are the symptoms? 2. When does it present? 3. Who does it effect? 4. General symptoms? 5. What is the treatment?

Answer 28

* 1. Akinesia (particularly involuntary movements of association and expression) * Rigidity/increased muscle tone * Tremor (sometimes one side only) 2. Takes three or more weeks to appear 3. Effects 1/3 patients on **typicals** 4. * Ridigity and trembling of the head and extremities * forward tilt of trunk * Reduced arm swinging * Shuffling gait with short steps 5. switch to **atypical** or decrease dose or commence **anticholinergic** eg procyclidine. * Use **anticholinergics** when indicated only (_toxic side-effects, fatal in overdose, may lower plasma levels of antipsychotics, have been abused, may exacerbate tardive dyskinesia_) * **Dopamine agonists** eg bromocriptine may be used to treat persistent rigidity/akinesia (theoretical risk of exacerbating psychosis)

Question 29

**Extra-Pyramidal Symptoms** 1. What is the mechanism for dystonia and parkinsonism? 2. What is the mechanism in tardive dyskinesia?

Answer 29

1. Imbalance between DA and Ach in the **striatum**. (Antipsychotic _reduces DA transmission_. Relative overactivity of cholinergic system) 2. denervation hypersensitivity occurs.There is **expression of additional DA receptors** at the synapse. Therefore an an _increase in DA activity in the striatum_. Relative underactivity of cholinergic system.

Question 30

**Akathisia** 1. Which type of antiP is it associated with? 2. What are the symptoms? 3. What is the treatment?

Answer 30

1. Typicals (50% patients) 2. Motor restlessness, subjective agitation, dysphoria or intolerance of inactivity. Associated with suicide. Mechanism unclear. 3. Reduce dose of antiP/switch to atypical 1. ​Poor response to anticholinergics, may respond to _propranolol or diazepam_

Question 31

**Tardive Dyskinesia** 1. Which patients are more likely to suffer from this? 2. When does it present? 3. Who is it more common in? When is it most severe? 4. What are the symptoms? 5. What is the proposed mechanism? 6. What is the treatment?

Answer 31

1. about 40-50% patients who have been treated long-term 2. Can take months or years 3. Women. Elderly + schizophrenics (even without antiP exposure). If an organic disease 4. Orofacial and buccal-lingual involuntary movements. Also choreoathetoid movements of upper and lower limbs, tics, abnormal posture, hemiballismus, grunting and disturbed respiration (other rare eg. “rabbit syndrome”) 5. Dopamine receptor **hypersensitivity**, induced by prolonged receptor blockade. 6. * Exacerbated by anticholinergics and by antiP withdrawal (increase may help temporarily) * Reduce/withdraw antipsychotic (and any associated anticholinergic)-initial exacerbation may be expected * Consider clozapine * Try benzodiazepine (eg clonazepam) or store depleting antipsychotic such as tetrabenazine * Open trials of many substances eg vitamen E but no clear evidence * Pallidotomy (creating a lesion to disrupt the pathway) in extreme cases

Question 32

What are the side effects related to other receptor mechanisms? 1. Anti-cholinergic 2. Anti-histamine 3. Anti-adrenergic 4. Sexual dysfunction 5. Weight gain 6. Neuroleptic malignant Syndrome

Answer 32

1. dry mouth, constipation, blurred vision 2. sedation 3. postural hypotension, sedation 4. 5-HT, alpha-2, anti-ACh 5. possibly 5-HT-2C antagonism 1. now a major problem with some atypicals (e.g.clozapine; olanzapine) 6. probably DA receptor syndrome

Question 33

What are some idiosyncratic side-effects of antiPs?

Answer 33

* **Cardiotoxicity** * prolongation of QTc interval increasing risk of arrythmias (esp. thioridazine and sertindole) * may be related to effects at K+ channels * **Hepatotoxicity** * persistent elevation of hepatic enzymes * seen more with older phenothiazine type * **Cholestatic jaundice** - mainly with chlorpromazine * **Photosensitivity** - mainly with chlorpromazine * **Skin pigmentation** - mainly with phenothiazines * **Blood dyscrasias** - possible with all but rare

Question 34

What are the indications for use of Antipsychotics? What are the non-psychiatric uses?

Answer 34

* Treatment of psychosis – applies to psychotic symptoms irrespective of the cause. * Sedation / reduction of agitation: * in severe ‘agitated’ depressive illness * occasionally in anxiety disorders –Nausea (pregnancy) –intractable hiccough –terminal illness –some forms of anaesthetic procedure

Question 36

What happens to antiP effect with dose?

Answer 36

increases After threshold, extra-pyramidal side effects are increased.

Question 37

**Clinical use of antiPs - ​Acute psychosis** 1. Name the oral antiP drugs 2. What does short term treatment often need? 3. How long for?

Answer 37

1. **Typicals** CHLORPROMAZINE 300-800 mg/day HALOPERIDOL 5-20 mg/day **Atypicals** RISPERIDONE 1-6 mg/day OLANZAPINE 5-20 mg/day 2. * **Benzodiazepine** for agitation or hostility, generally use **lorazepam**. * **Anticholinergics** may be necessary if pseudo-Parkinsonism (tremor, increased muscle tone) or akathisia (restlessness) develop. 3. 2-4 weeks for sustained improvement. If this doesn't occur: –is compliance good? –is dose adequate? –consider different drug

Question 38

**Clinical use of antiPs - ​Acute psychosis - MAINTENANCE** 1. How long are antiPs continued for after first acute episode? 2. When is long term maintenance therapy needed? 3. What are common depot drugs? 4. What does maintenance treatment achieve?

Answer 38

1. At least 1 year. Usually at a reduced dose, e.g. **chlorpromazine** 100-300 mg/day, olanzapine 10mg/day. 2. If established illness, with a history of relapse. This may be with a depot antipsychotic which ensures better compliance. 3. –**flupenthixol** 50 mg _every 2 weeks_ (20 mg/6 wks to 100 mg/wk) –**fluphenazine** 25 mg _every 2 weeks_ –**clopenthixol** haloperidol decanoate 4. greatly reduces the risk of recurrence, e.g. at one year after an acute episode 1. placebo maintenance 60-90% relapse active drug 10-40% relapse

Question 39

**AntiPs - Treatment Resistant Patients** 1. What proportion are resistant to treatment? 2. What should be tried?

Answer 39

1. Up to 30% 2. •Try at least two types of antipsychotic drugs, usually one ‘atypicals’ and one ‘typical’. * Try a depot antipsychotic. * Consider **clozapine**: –50% of resistant patients may respond.

Question 40

1. What is clozapine ONLY used for? 2. What are the problems? 3. Name some other adverse effects

Answer 40

1. treatment resistant patients 2. •5-10% develop low neutrophil count * 1% may develop agranulocytosis * Thus, careful monitoring of WBC count required. (Initially weekly; 2-weekly after 4 months and then 4-weekly after one year.) 3. –Marked postural hypotension initially –Marked sedation initially –Increased salivation

Question 41

Effect of widespread use of psychoharmaceuticals?

Answer 41

Numbers of patients in mental hospitals has greatly decreased Dramatic change began in 1956 with intro of antiPs