Drugs used in the treatment of psychoses

Department of Pharmacology, CSU

Zhang xiaojie

What are psychoses?

They are severe, chronic, disabling brain diseases
Major disturbances in reasoning, affection and behavior

Types of psychoses
1. Schizophrenia (split mind)
2. Affective disorders (Depression / Mania)
3. Anxiety

Schizophrenia
A clinical syndrome characterized by profound
disruption in cognition and emotion, affecting the most
fundamental attributes: language, thought, perception,
affect and sense of self

Positive Symptoms

Delusions
Hallucinations
Erratic/extreme emotions
Thought disorder

Negative Symptoms

Withdrawal from social contacts

Lack of interest/enjoyment in
activities
Blank facial expression, less
facial variability

Causes - Dopamine Hypothesis

Schizophrenia: with excessive dopaminergic activity

Evidences:
1.Drugs (L-dopa and amphetamine) that increase DOPA
can aggravate the symptom of schizophrenia
2.Dopamine receptor density in schizos
3.Anti-psychotic drugs block postsynaptic D2 receptor in
CNS
There is some evidence for involvement of 5-HT, and
possibly other mediators, such as glutamate

Classification of Antipsychotic drugs

Typical antipsychotics
Phenothiazines (chlorpromazine, perphenazine,
fluphenazine, thioridazine et al)
Thioxanthenes (flupenthixol, clopenthixol)
Butyrophenones (haloperidol, droperidol)

Atypical antipsychotics
(e.g. clozapine, risperidone, sulpiride, olanzapine)

Classification of Antipsychotic drugs

Distinction between typical and atypical

groups is not clearly defined, but rests on:

Incidence of extrapyramidal side-effects (less

in atypical group)
Efficacy in treatment-resistant group of
patients
Efficacy against negative symptoms.

Chlorpromazine: wintermine
Pharmacologic effects :
(1) CNS: a. neuroleptic effect
1. In animals: suppress spontaneous movements and
complex behaviors, but spinal reflexes remain intact
2. In normal humans: reduce initiative and interest,
produce drowsiness and slowness in response to
external stimuli
3.In psychotic patients: soon become less agitated,
aggressive and impulsive behavior diminishes.
Gradually, psychotic symptoms of hallucinations,
delusions, and disorganized thinking ameliorate.

Chlorpromazine
Pharmacologic effects :
(1)CNS:

b. antiemetic effect--- inhibit chemoreceptor trigger

zone or directly depress the medullary vomiting center,
but with no effect against nausea caused by vestibular
stimulation (motion sickness)

c. temperature-regulating effect--- produce

hypothermia with physical cooling

Chlorpromazine
Pharmacologic effects:

(2) autonomic nervous system: block adrenergic and M-Cholinergic receptors and
result in hypotension, dry mouth, constipation
and blurred vision.

(3) Endocrine system: increase the release of

prolactin and decrease corticotropin release
and secretion of pituitary growth hormone.

Mechanism: antidopaminergic action

Dopaminergic neuron pathway

1. Nigrostriatal pathway: extrapyramidal system adjust motor function
2. Mesolimbic pathway related to affection
3. Mesocortical pathway : related to cognition, reasoning and thinking
4. Tuberoinfundibular pathway :control the secretion of pituitary hormones

Dopamine receptors
Five subtypes of Dopamine receptors:
D1, D2, D3, D4, D5
D1 and D5 are named as D1 like receptor
Increase cAMP
D2, D3 and D4 are named as D2 like receptor
Decrease cAMP
D2 like receptor is highly related to schizophrenia

Mechanism of chlorpromazine
a nonspecific dopamine receptor blocker

Block

Block

Mesolimbic
Mesocortical

D2

Antipsychotic effects

Nigrostriatal
Tuberoinfundibular

D2

Adverse effects

Therapeutic uses
(1) treatment of psychotic disorders:
schizophrenia, mania, alcoholic hallucinosis.
(2) treatment of nausea and vomiting of certain
causes (digitalis, uremia, cancer)
(3) anesthesia in hypothermia and artificial
hibernation (used with pethidine and
promethazine)

Adverse Effects
1. Ordinary side effects
(1)Anticholinergic (antimuscarinic) side effects:
Dry mouth, blurred vision, urinary retention
(2)Antiadrenergic (Alpha-1) side effects:
Orthostatic hypotension w/ reflex tachycardia
(3)Antihistamine effect:
sedation, weight gain

Adverse Effects
2. Extrapyramidal side effects (EPS)
(1) Acute dystonisa :
spasm of muscles of tongue, face, neck, back, may
mimic seizures, during the first 1 -5 days of Rx
(2) Akathisia: motor restlessness
(3) Parkinson-like symptoms:
bradykinesia, rigidity, tremor, mask facies
Mechanism: nigrostriatal dopaminergic function
weakened, while cholinergic function strengthened
Treatment: anticholinergic :benzhexol

(4) Tardive dyskinesia :

involuntary movements of face and tongue, appearing
after months or years of antipsychotic treatment.
Mechanism:
Dopamine neurons reduce activity.
Postsynaptic D-2 receptor numbers increase
(compensatory response).
When D2 blockade is reduced, DA neurons resume
firing and stimulate increased of receptors >> hyperdopamine state >> tardive dyskinesia
Treatment:
increase neuroleptic dose; switch to clozapine

Atypical neuroleptics
Clozapine:
(1) be effective in treating some patients with psychosis
unresponsive to standard neuroleptic drug,effective
against negative symptoms
(2) blocks D4 receptor and have low affinity for D1 and
D2 dopamine receptors.
(3) lacks extrapyramidal side effects.
(4) must monitor the granulocyte counts weekly.

Risperidone:
(1)Highly effective against positive and negative symptoms
be used for first episode and chronic schizophrenia
(2)Dopamine-2 and Serotonin-2 receptor blockade
(3)EPS incidence is dose-related
Weight gain, prolactin elevation

Clinical Efficacy of
Antipsychotic Drugs

Antipsychotic drugs are effective in controlling

symptoms of acute schizophrenia, when large
doses may be needed.
Long-term antipsychotic treatment is often
effective in preventing recurrence of
schizophrenic attacks, and is a major factor in
allowing schizophrenic patients to lead normal
lives.

Clinical Efficacy of Antipsychotic Drugs

Long-acting preparations are often used for

maintenance therapy.
Antipsychotic drugs are not generally effective
in improving negative schizophrenic symptoms.
Approximately 40% of chronic schizophrenic
patients are poorly controlled by antipsychotic
drugs; clozapine may be effective in some of
these antipsychotic-resistant cases.

Anti-Manic Agents
Mania-- State of elevated mood and
psychomotor acceleration, with excess
catecholamines activity and decrease 5-HT
activity
Treatment: lithium carbonate

LITHIUM
PHARMACOKINETICS
ABSORPTION : virtually complete within 6 -8
hrs; peak plasma levels in 30 min to 2 hrs
DISTRIBUTION: in total body water; slow
entry into intracellular compartment. No
protein binding
METABOLISM: None
EXCRETION: virtually entirely in urine;
plasma half life is about 20 hours

lithium carbonate
Mechanism
Substitute for sodium in generating action potentials
Decrease norepinephrine & dopamine turnover
Block dopamine receptor supersensitivity
Enhance effects of serotonin

lithium carbonate
Adverse effects:
Nausea, vomiting and diarrhea.
Tremor.
Renal effect: polyuria (with resulting thirst)
Various neurological effects, progressing from
confusion and motor impairment , to coma,
convulsion and death.
narrow therapeutic limit for the plasma means
the monitoring is essential

Antidepressant
Depression Syndrome: depression, anxiety, tension,
bodily complaints, guilt (> 60%)

Types of antidepressant drug

Tricyclic antidepressant (TCA):

imipramine
amitriptyline

Selective 5-HT uptake inhibitors:

NE uptake inhibitors: desipramine
Atypical antidepressant: phenelzine

Fluoxetine,pa
roxetine,
sertraline

Imipramine
mechanism of action
to block NA and 5-HT reuptakes into the
presynaptic neurons to increase NA and 5HT level in the synaptic cleft in CNS.
Monoamine receptor densities in the brain
may change over 2 to 4 week with drug use
and may be important in the onset of activity.

Imipramine
Pharmacologic effects:
(1) CNS: a normal person experiences
sleeping. In the depressed patient, an
elevation of mood occurs 2-3 weeks after
administration begins.
(2) autonomic nervous system: anticholinergic
effects.
(3) cardiovascular effects: orthostatic
hypotension and arrhythmias.

Therapeutic uses
(1) Treatment of severe endogenous
depression (characterized by regression
and inactivity).
(2) Treatment of enuresis.
(3) Treatment of obsessive-compulsive
neurosis accompanied by depression, and
phobic-anxiety syndromes, chronic pain
and neuralgia.
Adverse effects: anticholinergic effects

Fluoxetine
Mechanism of action:
(1) is a selective inhibitor of serotonin uptake in the
CNS.
(2) has little effect on central norepinephrine and
dopamine function.
(3) has less adverse effects because of minimal
binding to cholinergic, histaminic, and adrenergic receptors.

Therapeutic uses:
(1) is used for treatment of mild to
moderate endogenous depression.
(2) be useful in treating obsessivecompulsive disorder, obesity.

Adverse effects:
(1) cause anorexia.
(2) precipitate mania or hypomania.
(3) result in nausea, nervousness,
headache, and insomnia.
(4) cause 5-HT syndromes
(hyperpyrexia, convulsions, and coma)
when combinated with and MAO
inhibitor.