This document discusses the treatment of psychosis and schizophrenia with a focus on antipsychotic drugs. It begins by classifying psychiatric disorders and defining psychosis. Schizophrenia is described as a particular type of psychosis characterized by disturbances in thinking. The dopamine theory of schizophrenia is explained, which posits that psychosis is related to increased dopamine activity in the brain. Older antipsychotics are dopamine antagonists that can cause neurological side effects like tardive dyskinesia. Atypical antipsychotics have fewer side effects. Lithium is discussed as the drug of choice for treating mania in bipolar disorder.

1. DRUG TREATMENT OF
PSYCHOSIS

2. Psychiatric Nosology
(Classification of disease)
• Psychosis
• Cognitive disorders: confusion, disorientation,
memory disturbances and behavioral disorganization
(delirium and dementia)
• Mood disorders
• Anxiety disorders
• Personality disorders

3. Psychosis
• Psychosis is a thought disorder
characterized by :
• Disturbances of reality and perception
• Impaired cognitive functioning
• Inappropriate or diminished affect (mood)
• Psychosis denotes many mental disorders.
 Schizophrenia is a particular kind of
psychosis characterized mainly by a clear
sensorium but a marked thinking disturbance.

4. Schizophrenia
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens early
twenties.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.

5. Schizophrenia
• It is a thought disorder.
• The disorder is characterized by a divorcement
from reality in the mind of the person
(psychosis).
• It may involved visual and auditory
hallucinations, delusions, intense suspicion,
feelings of persecution or control by external
forces (paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called “ideas of reference”.

6. Schizophrenia
Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms.
Apathy, social withdrawal, anhedonia (Loss of the
capacity to experience pleasure), emotional blunting,
cognitive deficits, extreme inattentiveness or lack of
motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.

8. Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.

9. Psychosis Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine

10. Dopamine Theory of Schizophrenia
Many lines of evidence point to the
aberrant increased activity of the
dopaminergic system as being critical in
the symptomatology of schizophrenia.

11. Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
psychosis.
• Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a
DA metabolite, in plasma, urine, and CSF.

12. Dopamine Theory of Schizophrenia
Evidence against the hypothesis
• Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in non-
schizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
receptors.
• Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.

13. Dopamine System
There are four major pathways for the dopaminergic
system in the brain:
I. The Nigro-Stiatal Pathway: Voluntary movements
II. The Mesolimbic Pathway.: Behaviour
III. The Mesocortical Pathway: Behaviour
IV. The Tuberoinfundibular Pathway: Prolactin release

14. THE DOPAMINERGIC SYSTEM
•THE DOPAMINERGIC SYSTEM

15. Catecholamines
Tyrosine
 Tyrosine hydroxylase
L-Dopa
 Dopa decarboxylase
Dopamine (DA)
 Dopamine  hydroxylase
Norepinephrine (NE)
(Noradrenaline) Phenylethanolamine-
 -N-methyltransferase
Epinephrine (EPI)
(Adrenaline)

16. Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine

17. Dopamine System
• DOPAMINE RECEPTORS
There are at least five subtypes of receptors:
Receptor
D1
D2
D3
D4
D5

18. Dopamine Reuptake System

19. Antipsychotic treatments
SCHIZOPHRENIA IS FOR LIFE
There is no remission

20. Antipsychotic treatments
Schizophrenia has been around perhaps, since the
beginning of humankind, however, it was not until
the last century that it was established as a separate
entity amongst other mental disorders.
Many treatments have been devise:
 Hydrotherapy:
“The pouring of cold water in a stream, from a height of
at least four feet onto the forehead, is one of the most
certain means of subsiding violent, maniacal excitement
that we have ever seen tried”... wrote an anonymous
physician in the early 1800’s.

21. Antipsychotics treatment
Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in
the prevention of psychosis.
• They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
• Schizophrenics must be treated with
medications indefinitely, in as much as the
disease is lifelong and it is preferable to
prevent the psychotic episodes than to treat
them.

22. Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are
drugs used mainly in the treatment of
schizophrenia, they are also used in the
treatment of :
– Psychoses associated with depression
– Manic-depressive illness
– Psychosis associated with alzheimer’s disease.
These conditions are life-long and disabling.

23. Antipsychotics/Neuroleptics
NON-compliance is the major reason for relapse.

24. Antipsychotic/Neuroleptics
Three major groups :
1. Phenothiazines
2. Thioxanthine
3. Butyrophenones
OLDER DRUGS

25. Antipsychotic/Neuroleptics
1) Phenothiazines
Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
• Aliphatic Piperidine Piperazine*
* Most likely to cause extrapyramidal effects.

26. Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines

27. Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the USA

29. Atypical Antipsychotic
Pimozide
Atypical Antipsychoitcs
Loxapine
Clozapine
Olanzapine
Qetiapine
Indolones
Sertindole
Ziprasidone
Olindone
Molindone
Risperidone

30. Antipsychotics/Neuroleptics
• Old antipsychotics
/neuroleptics are D2
dopamine receptor
antagonists.
Although they are
also effective
antagonists at ACh,
5-HT, NE receptors.
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
dopamine
receptor
antagonist
D2

31. Antipsychotics/Neuroleptics
• It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
• The affinities of most older “classical” agents
for the D2 receptors correlate with their
clinical potencies as antipsychotics.

32. Antipsychotics/Neuroleptics
• Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
• Clozapine has a higher affinity for the D4 receptors
than for D2.
• Recently it has been found that most antipsychotic
drugs may also bind D3 receptors (therefore, they
are non-selective).

33. Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor
activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors
(increased locomotion and stereotyped behavior).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of
prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
 hyperprolactinemia

34. Antipsychotic/Neuroleptics
[Drug dose]
Piperazine
Aliphatic
Piperidine

35. Antipsychotic/Neuroleptics
[Drug dose]
Phenothiazine d.
Thioxanthene d.
Butyrophenone d.

36. Antipsychotics/Neuroleptics
• Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.
• NE, GABA, Glycine and Glutamate have
also been implicated in schizophrenia.

37. Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why
their therapeutic effects are not evident until 4-8
weeks of treatment.
Blockade of D2 receptors

Short term/Compensatory effects:
 Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.
 DA synthesis, DA metabolism, DA release

39. Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects
 Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
 DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.

Receptor Supersensitivity

40. Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Neurological effects
b) Autonomic effects
c) Endocrine effects
d) Cardiac effects
3) Poor Concentration

41. Neurological effects
• Acute dystonia- Spasms of muscles of tongue,
neck and face
• Akasthisia – Uncontrolled motor restlessness
• Parkinsonism
• Neuroleptic Mallignant Syndrome
• Rabbit syndrome (perioral tremors)
• Tardive dyskinesia
Piperazines
Butyrophenones

42. Acute dystonia

43. Tardive Dyskinesia (TD)
• Repetitive involuntary movements, lips,
jaw, and tongue
• Choreiform quick movements of the
extremities
• As with Parkinson’s, movements stop
during sleep
• No effective treatment

45. The Nigro-Striatal Pathway
Inhibition
of
Motor Activity
DA
neuron ACh
neuron
GABA
neuron
GABA
neuron
Substantia
Nigra
+
-
-
-
-
Striatum

46. Antipsychotic/Neuroleptics
 Some antipsychotics have effects at
muscarinic acetylcholine receptors:
• Dry mouth
• Blurred vision
• Urinary retention
• Constipation
Clozapine
Chlorpromazine
Thioridazine

47. Antipsychotic/Neuroleptics
 Some antipsychotics have effects at -
adrenergic receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine
 Some antipsychotics have effects at H1-
histaminergic receptors:
• sedation
Risperidone
Haloperidol

48. Antipsychotic/Neuroleptics
 Blockade of D2 receptors in lactotrophs
in breast increase prolactin concentration
and may produce breast engorgement
and galactorrhea.

49. Blood Dyscrasias
• Clozapine 1-3 % incidence agranulocytosis
• Monitor WBC weekly
– WBC < 3,000 hold tx, check for infection
– Restart when reach 3,500
– WBC < 2,000 discontinue treatment, do not
rechallange

50. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of treatment
and shows no predilection for age, duration of
treatment, antipsychotic medication, or dose.

51. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
• Due to excessively rapid blockade of postsynaptic
dopamine receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with this
syndrome may be mistaken for an infection.
• Autonomic instability with altered blood pressure and
heart rate is another midbrain manifestation.
• Creatine kinase isozymes are usually elevated,
reflecting muscle damage.

52. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.

53. XVI. Anti-Manic Drugs
Lithium (Li+) remains the drug of choice for the
treatment and prophylaxis of mania.
• Acute manic episodes are managed with lithium
salts (carbonate or citrate) alone, or in combination
with:
1) Antipsychotics (carbamazepine, similar in
structure to TCAs but not effective in
depression).
2) Valproic acid
3) Calcium-channel blockers (nifendipine,
diltiazem, verapamil).

54. XVI. Anti-Manic Drugs
Li+
• Helps alleviate the depressive phase of
bipolar illness.
• Useful in refractory depression when
added to SSRIs or TCAs, but not a good
antidepressant alone.

55. XVI. Anti-Manic Drugs
Li+
Mechanism of action:
• Does not alter receptor numbers but alters the
coupling of the receptors with their second
messengers by reducing coupling of G-proteins.
• Regulation of -AR and DAR.
• Can reduce release of NTs (5-HT) and affinity of
binding to receptor.

56. XVI. Anti-Manic Drugs
Li+
Mechanism of action (Con’t):
Inhibits breakdown of IP2 to IP1 (during PIP
hydrolysis) => depletion of DAG and IP3 and 
[Ca2+] in response to receptor activation (i.e.
from 5-HT2R, 1-AR, muscarinic receptors and
others).
• Alterations in adenylate cyclase and
phospholipase C.

57. XVI. Anti-Manic Drugs
PIP
PIP2
G IP3
IP2
IP1
InositolPI
X Li+
PLC
DAG
Ca 2+