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Antipsychoti

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Prajogo Wibowo
School of Medicine - Hang Tuah University

Schizophrenia

DSM-IV-TR abbreviated criteria

2 or more of these for most of 1 month: delusions,


hallucinations, disorganized speech, grossly
disorganized or catatonic behavior, negative
symptoms
Social/occupational dysfunction
Duration of at least 6 months
R/o Schizoaffective and Mood disorders
R/o substance use & general med condition

DSM-IV-TR abbreviated criteria cont.

In the presence of pervasive developmental


disorders, must have prominent delusions or
hallucinations
Hallucinations and delusions [are] both symptoms
[that] reflect a loss of ego boundaries: the patient is
unable to distinguish between his or her own thoughts

Antipsychotics
Though the disease is not cured by
drug therapy, the symptoms of
schizophrenia, including thought
disorder, emotional withdrawal, and
hallucinations or delusions, may be
attenuated by antipsychotic drugs.
Unfortunately, protracted therapy
(years) is often needed and can result
in severe toxicity in some patients.1

Antipsychotic Classes
Phenothiazones, thioxanthenes, and
butyrophenones

Antipsychotic Classes
Atypically
Heterocyclics (more effective and less
toxic in some cases)
Clozapine [Clozaril]
Onlanzapine [Zyprexa]
Risperidone [Risperdal]
Quetiapine [Seroquel]
Ziprasidone [Geodon]
Etc.

Mechanism of Action
Dopamine hypothesis
Excess of dopamine in specific neural tracts
D2 receptor is in the caudate putamen, nucleus
accumbens, cerebral cortex, and hypothalamus

Many antipsychotics block the D2 receptor


Dopamine agonists exacerbate schizophrenia
Increased density of dopamine receptors in
the brains of untreated schizophrenics

Mechanism
of Action
Dopamine pathways
Mentation & Mood
Mesocortical
Mesolimbic

Extrapyramidal Function
Nigrostriatal

Prolactin release
Tuberoinfundibular

Emesis
Chemoreceptor trigger zone
3

Mechanism of Action

Other receptors

Clozaril has low D2 affinity but significant D4 and 5-HT2


(serotonin) receptor blocking actions
Most atypicals have high 5-HT2A affinity and may also interact
with D2 and other receptors

Desirable Effects
Reduction of positive symptoms
Hyperactivity, bizarre ideation, hallucinations, delusions
Typicals and atypicals reduce positive symptoms

Improve negative symptoms


Emotional blunting, social withdrawal
Atypicals

Also reduces psychotic symptoms in schizoaffective


disorder, Tourettes syndrome, toxic psychoses
Except thioridazine phenothiazines have antiemetic
properties via H1 blocking

Adverse Effects
Reversible parkinsonism, akathisias, and dystonias
Treatment is to decrease antipsychotic dose or use
muscarinic blocking agents
Less common with atypicals

Tardive dyskinesias
Develop within 6 months to several years of therapy
Antimuscarinics increase TD severity
May be caused by dopamine receptor sensitization because
increasing antipsychotic doses temporarily attenuates
symptoms
May be irreversible
No pharmacological treatment

Adverse Effects
Autonomic effects

(tolerance may develop with continued therapy)

Muscarinic blockade dry mouth, constipation, urinary


retention, visual problems
Alpha adrenergic receptor blockade postural hypotension,
failure to ejaculate

Endocrine and metabolic effects


Hyperprolactinemia, amenorrhea, galactorrhea, infertility,
weight gain, gynecomastia

Neuroleptic Malignant Syndrome


Muscle rigidity, impairment of sweating, hyperpyrexia,
autonomic instability
May be life threatening
Treat with dantrolene and possibly dopamine agonists

Adverse Effects
Sedation
More marked with phenothiazines
Except for sertindole, all atypicals block histamine receptors

Miscellaneous toxicities
Thioridazine retinal deposits causing visual impairments, high
doses leads to fatal ventricular arrhythmias
Sertindole prolonged QT segment leading to arrhythmias
Clozapine 1-2% incidence of agranulocytosis, seizures at high
doses

Overdose toxicity
Other than thioridazine (cardiotoxicity), overdoses are usually
not fatal
Lowers seizure threshold
Hypotension responds to fluid replacement