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Trihexphenidyl Plus Risperidone

Dr Amita Birla
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Psychiatric disorders
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%
% of
of adults
adults with
with severe
severe mental
mental
disorders
disorders

Diagnosis %
Schizophrenia 1.5
Bipolar disorder 1.0
MDP 1.1
Panic disorder 0.4
OCD 0.6
Mosby’s Adult Psychiatry, 2005
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Schizophrenia

A mental disorder which interferes

with a person’s ability to think
clearly, manage emotions, make
decisions and relate to others
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Two or more of the foll present for a significant portion of
time during a 1month period

• Delusions
• Hallucinations
• Disorganised speech
• Grossly disorganised behaviour
• Negative symptoms

These symptoms affect social and occupational

functioning
Continuous disturbance persisting for at least 6 months
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Psychiatric Disorder

• Bipolar
– On extremes- Depression and Mania
• Mania
– ("to rage, to be furious") is a severe medical condition
characterized by extremely elevated mood, energy,
unusual thought patterns and sometimes psychosis
• Autism
– a brain development disorder characterized by
impaired social interaction and communication, and
by restricted and repetitive behavior
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DOPAMINERGIC TRACTS

The most important dopaminergic tracts in

psychiatry are :
i. The Mesolimbic tract (D2): assoc with +ve symptoms
ii. The Mesocortical tract (D1): assoc with -ve symptoms
ii. The Nigrostriatal tract: assoc with EPS
ii. The tuberoinfundibular tract: assoc with
Gynaecomastia
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THE NERVOUS SYSTEM

BASAL GANGLIA :

• Small islands of gray matter deep in white matter of brain

• Consists of
- Caudate Nucleus
- Putamen
- Globus Pallidus
- Substantia Nigra
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THE NERVOUS SYSTEM

LIMBIC SYSTEM :
• Consists of Limbic lobe, Amygdala, Septal nuclei,
Hypothalamus, Anterior thalamic nuclei.
• Lies below the cerebral cortex
• Integrates emotional state with motor and visceral activity
• Along with hypothalamus it is concerned with sexual
behaviour, emotions of rage,fear & motivation
• Excessive dopamine in mesolimbic system associated with
schizophrenia.
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Correlation of dopamine activity with positive
& negative symptoms of schizophrenia

+
Increase levels
Increase levels in
in the
the
limbic system
limbic system
(Mesolimbic
(Mesolimbic
Pathway)
Pathway)

-
Decreased activity
Decreased activity in
in
the prefrontal
the prefrontal cortex
cortex
(Mesocortical
(Mesocortical
pathway)
pathway)
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Pathways Symptoms Neuro- Remarks

Transmitters
1) MESOLIMBIC +ve DA > 5HT Hallucination,
Delusions seen
2) MESOCORTICAL -ve 5HT > DA Apathy,
social withdrawal
seen
3) NIGROSTRIATAL SIDE- ACH > DA E.P.S.
EFFECT
4) TUBERO- SIDE- PROLACTIN Gynaecomastia
INFUNDIBULAR EFFECT >DA
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Antipsychotics - Classification

Typical
Atypical
or
Conventional
Chlorpromazine Thioridazine Clozapine, Olanzapine
Trifluoperazine, Haloperidol Risperidone
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Atypical antipsychotics

Olanzapine Clozapine Quetiapine

Serotonin- Dopamine
Antagonists (SDA’s)

Risperidone Sertindole Ziprasidone

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D2 blockade
Preferentially block D2 receptors is the mesolimbic
system, sparing the nigrostriatal& pituitary
pathways

Better control of positive symptoms

Lesser
Lesser EPS
EPS Lesser
Lesser hyperprolactinemia
hyperprolactinemia
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5HT2 : D2 blockade
Preferentially block 5-HT2a receptors in the
mesocortical system

Stimulates Dopamine activity in cortex

Better control of negative symptoms

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Risperidone

• Risperidone has a greater affinity for the

dopamine D2 receptor than for the D1
receptor,

• Its D2/5-HT2 affinity ratio is low.

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Haloperidol v/s Risperidone

Pathways HALOPERIDOL RISPERIDONE

1) MESOLIMBIC ++ ++
2) MESOCORTICAL _ +
3) NIGROSTRIATAL ++ +

4) TUBERO- + _
INFUNDIBULAR
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Conclusion :
 Risperidone is a weaker binder of DA and hence
weak DA antagonist. Haloperidol is a strong DA
antagonist. (D2 receptor occupancy with risperidone in
the limbic-cortical regions seems to be similar to that of
previous reports regarding the striatum, and it would be
comparable to that of typical antipsychotics.)

 Risperidone has less S/E like EPS and

Gynaecomastia as compared to Haloperidol.
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Risperidone Vs Haloperidol
• In the short-term and long term, risperidone was more
likely to produce an improvement in the Positive and
Negative Syndrome Scale (PANSS) when compared with
haloperidol

• Risperidone was also more likely to reduce relapse at

one year follow up, compared with haloperidol

• Less people allocated risperidone left studies before

completion, both for short-term and long-term trials.
For general movement disorders results favoured
risperidone. People given risperidone had significantly
fewer general movement disorders (including
extrapyramidal side effects) than those receiving older
typical antipsychotics

• Cochrane Database of Systematic Reviews 2003, Issue 1

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Risperidone Vs Olanzapine

 People allocated to risperidone were less likely

to gain weight compared with those given
olanzapine and the weight gain was often
considerable and of quick onset. Risperidone
participants were less likely to leave the study
due to metabolic side effects and weight gain
compared with olanzapine

 Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005237. DOI:
10.1002/14651858.CD005237.pub2
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Risperidone - ADRs
• Insomnia, anxiety, agitation, sedation,
dizziness, rhinitis, hypotension, weight gain,
and menstrual disturbances

• Does not produce granulocytopenia or

agranulocytosis, so no weekly monitoring is
required, as is the case with clozapine
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Use

• Schizophrenia
• Short-term treatment of the mixed and
manic states associated with bipolar
disorder
• Irritability in children and adolescents
with autism
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Non approved uses
• Anxiety disorders, such as obsessive-
compulsive disorder;
• Severe, treatment-resistant depression with or
without psychotic features;
• Tourette syndrome;
• Disruptive behavior disorders in children; and
• Eating disorders,
• Symptoms of phencyclidine psychosis due to
acute intoxication and chronic use.
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Pharmacokinetic
• Rapidly and completely absorbed
• Reaches peak plasma levels within 2 hr
• Extensively metabolized in the liver
• 9-hydroxyrisperidone, the major
metabolite, has a half-life of 17 to 22 hr
compared to 2 to 4 hr (mean 2 to 8 hr)
for risperidone
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Dosage
• Risperidone, in doses of 4 to 10 mg/day,
appears to be at least equivalent and possible
superior to haloperidol, 10 to 20 mg/day, in
decreasing positive and negative symptoms

• The usual starting dose of risperidone is 1 mg

twice daily, increasing to 2 mg twice daily and 3
mg twice daily over the next 2 days
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Dosage
• The mean optimal dose appears to be 6 mg/day
but higher doses may be needed to control
positive symptoms in some patients.

• In a recent study, risperidone was superior to

placebo as add-on-therapy to typical
neuroleptic drugs in mentally retarded patients
with persistent behavioral disturbances. This
may reflect the value of 5-HT2 antagonism as a
supplement to D2 receptor blockade.
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Low Dose Risperidone

• Low-dose risperidone may be an effective

treatment for anxiety disorders in which
panic attacks are a significant
component.

BMC Psychiatry 2009, 9:25

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Double-blind trials of risperidone in bipolar disorder
Authors Study phase Number ofDuration Efficacy results
subjects

Segal et al (1998) mania: monotherapy 4528 days risperidone = haloperidol = lithium

Sachs et al (2002) mania: mixed combination 1563 weeks risperidone, haloperidol > placebo
with mood stabilizer

Yatham et al (2003)
mania: mixed combination
with mood stabilizer
Hirschfeld et al (2004)
mania: monotherapy
1513 weeks risperidone = placebo excluding
carbamazepine group
risperidone + mood stabilizer > mood
stabilizer alone
2593 weeks risperidone > placebo

Petrie et al (2004) mania: mixed combination 378 weeks risperidone = olanzapine

with mood stabilizer

Khanna et al (2005)
mania: mixed monotherapy 2903 weeks risperidone > placebo

Smulevich et al (2005)
mania: mixed monotherapy 4383 weeksa risperidone > placebo
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TRIHEXPHENIDYL
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TRIHEXPHENIDYL

• It is a direct inhibitor of the

parasympathetic nervous system and
exerts a direct inhibitory effect upon the
smooth musculature
• It also improves psychotic depression and
mental inertia
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Pharmacokinetics

• Trihexyphenidyl is rapidly absorbed

from the gastrointestinal tract.
• The onset of action is within 1 hour
• The peak activity is after 2 to 3 hours.
• The duration of action is 6 to 12 hours
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Therapeutic Use
• Parkinson's disease in mono- and combination
therapy

• Treat extrapyramidal side effects occurring

during antipsychotic treatment. It reduces the
frequency and duration of oculogyric crises as
well as of dyskinetic movements and spastic
contractions.
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Contraindications
• Hypersensitivity to trihexyphenidyl
• Narrow angle glaucoma
• Ileus
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Side-effects
• CNS : Drowsiness, vertigo, headache, and dizziness are
frequent. With high doses nervousness, agitation, anxiety,
delirium, and confusion are noted. Trihexyphenidyl may
be abused due to a short acting mood-elevating and
euphoriant effect. The normal sleep architecture may be
altered (REM sleep depression). Trihexyphenidyl may
lower the seizure-threshold.

• Tolerance may develop during therapy which requires

dose adjustments.
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Side effects
• Peripheral side effects : Blurred vision,
dry mouth, impaired sweating,
abdominal discomfort, and constipation
are frequent. Tachycardia may be noted.
Allergic skin reactions may occur.
• Eyes : Trihexyphenidyl causes mydriasis
with or without photophobia. It may
precipitate narrow angle glaucoma.
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Dosage

• Extrapyramidal side effects : Usually, 5

to 15 mg daily are needed in 2 or 3
divided doses. Some patients, however,
are successfully treated with as little as
1 mg daily
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Sizomax T3 and T4

Trihexphenidyl Plus Risperidone

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Rationale

• Risperidone blocks the D2 receptor in the

Nigrostrital pathway which is the part of the
basal ganglion which is the structure in the
brain responsible for maintenance of muscle
tone, posture and equilibrium
• Dopamine and acetyl choline are the two
important neurtransmitter of the basal
ganglion.
• With blockage of dopamine the acetyl choline
activity in the region increases leading to
unwanted extrapyramidal symptoms.
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Rationale
• Trihexphenidyl is a direct inhibitor of the
parasympathetic nervous system and exerts a direct
inhibitory effect upon the smooth musculature

• Thus by combining the two the severity of the EPS is

taken care of which is one of the main reasons for patient
withdrawal.

• Also, It improves psychotic depression and mental inertia

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Dosage form And Dosage

• Risperidone: 3 mg
Trihexphenidyl: 2 mg

• Risperidone : 4 mg
Trihexphenidyl: 2 mg

• Dosage: 1 tab BD
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Therapeutic use

• Schizophrenia
• Short-term treatment of the mixed and
manic states associated with bipolar disorder
• Irritability in children and adolescents with
autism
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Thank you friends