Schizophrenia/Antipsychotics

Wednesday, November 11, 2015

4:34 PM

SCHIZOPHRENIA/ANTIPSYCHOTICS
Ch. 20
Ch. 22 BP
- Schizophrenia: problems with thought processes and emotional responsiveness.
- Two types of symptoms:
Positive Symptoms.
Negative Symptoms.
Delusions.
Flat affect (absence of emotional speech).
Hallucinations (esp. auditory).
Social withdrawal (asociality).
Disorganized speech.
Poverty of speech (alogia).
Disorganized behavior (catatonia). Anhedonia.
Dopamine Hypothesis of Schizophrenia:
- 'Excessive' dopaminergic activity in mesolimbic system.
Drugs that increase DA in limbic system cause symptoms of psychosis or aggravate existing schizophrenia (e.g. cocaine,
amphetamines, levodopa, bromocriptine).
In untreated schizophrenia, postmortem studies show increased number of DA receptors (D1-like and D2-like).
The increased # of receptors may be due to diminished DA synthesis or release in limbic and cortical areas.
- Tx: typical antipsychotics (antagonize D2 receptors, thus cAMP).
Serotonin Hypothesis of Schizophrenia:
- Hallucinogens such as LSD and Mescaline mimic findings of schizophrenia, by stimulating 5-HT2A receptors.
- Serotonin modulates DA (and glutamate) neurotransmission:
5-HT inhibits DA release through 5-HT2A.
If we inhibit 5-HT2A receptors, DA levels will increase.
The net effect depends on brain area and receptor densities:
Nigrostriatal pathway: decreased extrapyramidal symptoms (EPS).
Mesolimbic pathways have more D2-like receptors than 5-HT2A receptors: blocking 5-HT2A receptors does not increase DA
enough to overcome effects of D2 blockade (weak D2 blocker but nevertheless does the job). This will decrease positive
symptoms of schizophrenia.
Mesocortical pathway: increase DA, overcome dysphoric effect of D2 blockade, improve negative symptoms of schizophrenia.
Tuberoinfundibular pathway: increase DA release, oppose hyperprolactinemia of D2 antagonists.
- Tx: atypical antipsychotics (weak D2 blocker, strong 5-HT2A receptor blockers).
Glutamate Hypothesis of Antipsychotics:
- Drugs such as PCP (phencyclidine) and ketamine block NMDA receptors, and cause psychosis.
- NMDA receptors are found on GABA neurons, and their stimulation will increase GABA release.
Schizophrenia is associated with decreased NMDA signaling (hypofunction) and decreased inhibitory influences from GABA.
- Newer drugs are being developed to NMDA funtion or regain the normal inhibitory influences of GABA.
Extrapyramidal Symptoms (EPS) due to D2 receptor blockade. Mnemonic is ADAPT (Acute Dystonia, Akathisia, Parkinsonism, Tardive
Dyskinesia).
- 4 are early onset:
Acute dystonic reactions: muscle spasms of tongue, face, neck, and back.
Tx: antimuscarinic drugs (benztropine, diphenhydramine).
Akathisia: due to the blockade, receptors become more sensitized. Motor restlessness.
Tx: dose reduction of antipsychotics. Non-selective beta blockers, antimuscarinic drugs, or benzodiazepines help.
Drug Induced-Parkinsonism: bradykinesia, rigidity, resting tremor.
Tx: antimuscarinic drugs.
Neuroleptic Malignant Syndrome (NMS): secondary to central effect on temperature control and motor control.
Think FEVER:
Fever.
Encephalopathy (catatonia, stupor).
Vitals unstable (CV instability).
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 Vitals unstable (CV instability).

Enzymes increased (myoglobinemia). There might be elevated creatine kinase (CK) due to rhabdomyolysis, and also
hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia.
Rigidity of muscles ('lead-pipe rigidity').
Tx: dantrolene (to reduce muscle rigidity) + bromocriptine. Stop antipsychotics immediately.
- 2 are late onset: years later.
Perioral tremors: 'rabbit syndrome'. Antimuscarinic drugs may help.
Tardive Dyskinesia: often irreversible. Upregulation and sensitization of D2 receptors. Oral and facial dyskinesia with chorea and
athetosis.
No treatment.
Atypical antipsychotics are less likely to cause tardive dyskinesia.

Side Effects of Antipsychotics:

- All antipsychotics are muscarinic antagonists (atropine-like):
3 Cs: coma, convulsion, cardiotoxicity (Torsades).
- 1-antagonism (Prazosin-like):
Lowers BP, Orthostatic hypotension, reflex tachycardia.
Sexual dysfunction.
- H1 (serotonin) antagonism: sedation, weight gain.

Typical Antipsychotics
(neuroleptics).
High-potency
neuroleptics: Try to Fly
High.
- Trifluoperazine.
- Fluphenazine.
- Haloperidol.
- Pimozide.
Low-potency
neuroleptics (less likely
to cause EPS, but more
ANS effects): Cheating
Thieves are low.
- Chlorpromazine.
- Thioridazine.
Fluphenazine.
Haloperidol.

Mechanism: Block D2 receptors Indication: schizophrenia

in mesolimbic pathway, to
(primarily decrease
decrease positive symptoms.
positive symptoms).
Psychosis.
They worsen negative symptoms Bipolar Disorder.
Delirium.
because DA is already low in
mesocortical pathway, so D2
Tourette Syndrome.
blockade will lead to underactive
pathway, and negative
symptoms (source).

Exists in depot form (IM).

Potent D2 blockade.

Pimozide.

Acute management of
psychosis and mania
('tranquilizer').

Severe EPS, including NMS

(neuroleptic malignant syndrome)
and tardive dyskinesia.
Caution in seizure patients.

Tourette syndrome and

tic disorders.

Chlorpromazine.

Thioridazine.

Adverse effects:
Blocks mesocortical pathway:
worsen negative symptoms by
causing dysphoria (this
compliance).
Blocks nigrostriatal pathway:
causes extrapyramidal symptoms
(EPS), such as dyskinesia, dystonia,
Parkinsonism.
Endocrine effects due to blockade
of tuberoinfundibular pathway:
hyperprolactinemia,
gynecomastia, oligomenorrhea,
and weight gain.

Prominent ANS side effects.

QT prolongation.
Deposits in Cornea (phototoxic).
Strongest antimuscarinic effect:
likely to cause Torsades.
Deposits in reTina.

'Auto treats' acute EPS.

Atypical Antipsychotics. Mechanism: weak D2 blocker,

strong 5-HT2A receptor
blockers.
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Indication: 1st line for

schizophrenia (decrease
positive symptoms, and
improve negative

Adverse effects:
Fewer EPS and anticholinergic side
effects vs Typical Antipsychotics.
Fewer hyperprolactinemia effects.

Clozapine.

Strong D4 (common in
mesolimbic) and 5-HT2A
receptor blocker.

Olanzapine.

Strong 5-HT2A blocker.

Improves negative symptoms.

Risperidone.

Strong 5-HT2A blocker.

Aripiprazole (Abilify).

Partial agonist of D2 receptors.

5-HT2A antagonist.
5-HT1A partial agonist (like
Buspirone).
Strong H1 and 1 antagonism.
No antimuscarinic antagonism.
Strong blocker of 5-HT1,2,6,7
receptors.
Also blocks all subtypes of DA
receptors.
Blocks 5-HT and NE reuptake.

Quetiapine (Seroquel).
Ziprasidone.

Tourette: fluphenazine, pimozide, tetrabenazine.

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improve negative
symptoms).
Levodopa-induced
psychosis.

Fewer hyperprolactinemia effects.

May prolong QT interval.
Agranulocytosis (weekly CBC
blood test and focus on WBC).
Watch bone marrow clozely.
No EPS, no tardive dyskinesia.
Weight gain, seizures.
Hypersalivation ('wet pillow
syndrome'): serotonin causes
increased secretions.
Alternative to clozapine. Metabolic syndrome: weight gain
(Obesity), Diabetes,
Hyperlipidemia.
- With any "-pine", there is risk of
metabolic syndrome.
seizures.
Hypotension from 1 blockade.
Hyperprolactinemia (amenorrhea,
galactorrhea, gynecomastia):
prolactin inhibits GnRH, thus
decreasing LH and FSH release.
Also for mania associated Headache, dizziness, nausea and
with bipolar disorder,
vomiting, insomnia.
autism.

Cataracts.