Shizophrenia

1. Schizophrenia
BY
Dr. Sajjad Ali
Pharm-D, R.Ph., M.Phil. Pharmacology

2. Objectives
 Schizophrenia
 Dopamine hypothesis of schizophrenia
 Antipsychotic/neuroleptic drugs
 Phenothiazine derivatives
 Thioxanthine derivatives
 Butyrophenone derivatives
 Atypical neuroleptics

3. Schizophrenia
 Schizophrenia is a mental disorder
characterized by abnormal social behavior and
failure to understand what is real.
 Common symptoms include false beliefs,
unclear or confused thinking, hearing voices
that others do not, reduced social
engagement and emotional expression and a
lack of motivation.

5.  Pathogenesis of schizophrenia is unknown
Dopamine Hypothesis of schizophrenia:
 Excessive dopaminergic activity plays a role in the
schizophrenic disorder developments
 This hypothesis is supported by following evidences
1. Many antipsychotic drugs strongly block postsynaptic
D2 receptors in CNS
2. Drugs that increase dopaminergic activity, such as
levodopa, amphetamines and apomorphine either
aggravate schizophrenia or produce psychosis

6. 3. Dopamine receptor density have been found
to be increased in postmortem reports in the
brains of schizophrenic patients
4. Positron emission tomography (PET) has
shown increased dopamine receptor density
in both treated and untreated schizophrenic
patients as compared to non schizophrenic
patients

7.  Dopamine hypothesis is far from complete
 If an abnormality of dopamine physiology
were completely responsible for the
pathogenesis of schizophrenia, antipsychotic
drugs would do a much better job of treating
patients
 However, they are only partially effective for
the most of the patients and ineffective for
some patients

8. Antipsychotics/neuroleptics
 Terms antipsychotic and neuroleptic have
been used interchangeably to denote a group
of drugs that have been used for the
treatment of schizophrenia

9. Neuroleptic drugs
Typical
(classic drug)
Phenothiazines
class
Chlorpromazine
Thioridazine
Fluphenazine
Thioxanthenes
class
Thiothixene
Butyrophenones
class
Haloperidol
Atypical
(newer agent)
Heterocyclic
structure
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone

10. D2 receptorD2 receptor
Typical
-
Atypical
-
5-HT2A receptor
Atypical
-
Typical is D2 antagonist Atypical is serotonin-dopamine antagonist
high affinity to D2 high affinity to 5-HT2ALow affinity to D2
Binding to D2 receptor
(tight)
Binding to D2 receptor
(loose)
Atypical dissociate rapidly from D2 receptor

11. • first-generation ('typical') antipsychotics (e.g.
chlorpromazine, haloperidol, fluphenazine and
thioridazine)
• second-generation ('atypical') antipsychotics (e.g.
clozapine, risperidone, quetiapine, aripiprazole etc.).
• Distinction between typical and atypical groups is not
clearly defined but following difference is significant
• Incidence of extrapyramidal side effects (less in atypical
group)

12. Typical antipsychotic drugs
 They have an equal or greater affinity for D2
receptors than for 5-HT2 receptors
 Antagonism of D2 receptors in mesolimbic
pathways suppress the positive symptoms of
Schizophrenia
 Blockade of D2 receptors in the basal ganglia
is responsible for parkinsonian and other
extrapyramidal side effects of anti psychotic
drugs

13. Phenothiazines
• Chlorpromazine, Fluphenazine, Thioridazine
• Similar therapeutic effects
• Different potency and side effect
• Chlorpromazine And Thioridazine lower
potency, more autonomic side effects and
fewer extrapyramidal side effects than high
potency drugs
• Fluphenazine has Higher potency

14. Phenothiazines
 Blockade of D2 receptors
 Positive symptoms of Schizophrenia Decrease
in 1-3 weeks
 Less agitated, fewer auditory hallucinations
 It causes Behavioural improvement

15. Indication of Phenothiazine
• Schizophrenia
• Drug-induced psychosis
• Psychosis associated with the manic phase of
bipolar disorder.
• Dementia
• Severe mental retardation
• Some of them for management of nausea and
vomiting

16. Butyrophenones (Haloperidone)
• Haloperidol has
pharmacological effects
similar to fluphenazine.
• It is available in a long
acting depot.
• It is used for treatment
of schizophrenia and
Tourette’s syndrome .
Tourette’s syndrome is a
neurological disorder
characterized by
repetitive, stereotyped,
involuntary movements
and vocalizations called
tics

17. Atypical antipsychotic drugs
These includes;
Clozapine
Olanzapine
Ziprasidone
Risperidone
quetiapine
They have a greater affinity for 5-HT2
receptors than for D2 receptors

18. Olanzapine
 Olanzapine is superior to haloperidol in
alleviating of negative symptoms.
 Fewer extrapyramidal side effects
 At high doses may cause akathisia,
pseudoparkinsonism, and dystonias.

19. Risperidone
• Its pharmacological effects are similar to
olanzapine.
• But less sedation more orthostatic
hypotension, higher incidence of
extrapyramidal side effects.

20. Clozapine
 Clozapine has fewer extrapyramidal side effect
and greater activity against negative
symptoms and its use is with 1.3% first year
incidence of potentially fatal agranulocytosis.

21. Other Actions of Antipsychotic drugs
Antiemetic effects:
 With the exceptions of aripiprazole and
thioridazine most of neuroleptics have
antiemetic effects mediated by blocking of D2
receptors of chemoreceptor trigger zone of
medulla.
Antimuscarinic effects:
 Some of neuroleptics such as thioridazine,
chlorpromaine, cloapine and olanapine produces
anticholinergic effects

22. Other Effects of Neuroleptics
 Alpha-1 adrenergic blocking effects causing
orthostatic hypotension
 They also alter temperature regulation
mechanism
 Elevation of prolactin level
 Atypical neuroleptics less likely cause
elevation of prolactin level
 They also have H1 blocking effects thus
causing sedation

23. Therapeutic Uses of Neuroleptics
 Treatment of schizophrenia
 Prevention of nausea and vomiting
 They can be used as tranquilizers to manage
agitation secondary to other disorders

24. Adverse side effects of anti-psychotics
Common side effects are;
 Tremors
 Postural hypotension
 Constipation
 Urinary retention
 Confusion
 Sexual dysfunctions

25. Adverse effects
1- Extrapyramidal side effects
-Acute:
 Akathisia (Motor restlessness)
 Pseudoparkinsonism
 Dystonias (Sustained contraction
of muscles leading to twisting
distorted postures)
-Chronic:
 Tardive dyskinesia (Involuntary
movements of lips, neck, trunk,
tongue and libs)
Tardive dyskinesia

26. Dystonias Akathisia
• Akathisia is 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.

27. 2- Neuroleptic malignant syndrome
3-Increase serum prolactin levels
4-Impair thermoregulation cause poikilothermy

28. Neuroleptic malignant syndrome (NMS) is a life-
threatening idiosyncratic reaction to
antipsychotic drugs characterized by;
 Fever
 Altered mental status
 Muscle rigidity and
 Autonomic dysfunction

29. Atypical neurolepticTypical neuroleptic
• 5-HT2A antagonist
• D2 antagonist
• Rapid D2 Dissociate
D2 antagonistMechanism of Action
Antagonism of H1, M1,
5-HT2c, alpha 1 receptor ,
among other
Antagonism of H1, M1,
alpha-1 receptor ,
among other
Other effect
Summary