Complete description of disease with detailed pathophysiology and advanced management

1. Prepared by : Ruchita Bhavsar
1st year M. Pharm
Guided by : Mr. Samaresh Pal Roy
Asst. Prof. of Pharmacology

2. CONTENT
• Introduction
• Etiology
• Epidemiology
• Types
• Signs and symptoms
• Pathophysiology
• Complication
• Diagnosis
• Prognosis
• Management
• Adverse Effects
• Drug Interaction
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3. INTRODUCTION
• Schizophrenia literally means “Fragmented Mind”.
• Schizophrenia is one of the most complex, chronic and challenging of
psychiatric disorders that affects how a person thinks, feels, behaves.
• It represents a heterogeneous syndrome of disorganized thoughts,
delusions, hallucinations, and impaired psychosocial functioning.
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4. ETIOLOGY
• While many factors have been associated with developing
schizophrenia—including genetics, early environment, neurobiology, and
psychological and social processes—the exact cause of the disease is
unknown.
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5. 1. Viral Infections and Immune Disorders :
• Schizophrenia may be triggered by environmental events, such as viral
infections or immune disorders. For instance, babies whose mothers get
the flu while they are pregnant are at higher risk of developing
schizophrenia later in life. People who are hospitalized for severe
infections are also at higher risk.
2. Genetics (Heredity) :
• Scientists recognize that the disorder tends to run in families and that a
person inherits a tendency to develop the disease. Similar to some other
genetically-related illnesses, schizophrenia may appear when the body
undergoes hormonal and physical changes.
• The risk of developing schizophrenia is increases to approximately 10% if
a first-degree relative has the illness and to 3% if a second-degree
relative has the illness. If both parents have schizophrenia, the risk of
producing a schizophrenic offspring increases to approx 40%.
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6. EPIDEMIOLOGY
• The prevalence of schizophrenia ranges from
0.6% to 1.9%, with an average of
approximately 1%
• Schizophrenia most commonly has its onset
in late adolescence or early adulthood and
rarely occurs before adolescence or after the
age of 40 years. The peak ages of onset are
20–38 years for males and 26–32 years for
females.
• Slightly more men are diagnosed with
schizophrenia than women (on the order of
1.4:1) and women tend to be diagnosed later
in life than men.
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7. TYPES
• Paranoid schizophrenia
• Common form of schizophrenia
• Prominent hallucinations and/or delusions
• May develop at a later age than other types of schizophrenia
• Speech and emotions may be unaffected
• At risk for suicidal or violent behavior under influence of delusions
• Hebephrenic / Disorganized schizophrenia
• Behaviour is disorganised and without purpose
• Thoughts are disorganised, difficult to understand by others
• Pranks, giggling, health complaints, grimacing and mannerisms are
common
• Delusions and hallucinations are fleeting
• Usually develops between 15-25
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• Catatonic schizophrenia
• Rarer than other types
• At risk for malnutrition, exhaustion or self-injury
• Unusual movements, often switching between extremes of over-
activity and stillness
• Unable to talk (Catatonia)
• Undifferentiated schizophrenia
• Some characteristics of paranoid, hebephrenic or catatonic
schizophrenia, but does not obviously fit one of these types
• Residual schizophrenia
• Past History of psychosis but only having negative symptoms

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10. SIGNS & SYMPTOMS
Positive Symptoms
• DELUSION : False beliefs that are not based in reality
• HALLUCINATION : Involving seeing or hearing things that don't exist
• DISORGANIZED SPEECH & THINKING : Effective communication can
be impaired and answers to questions may be partially or completely
unrelated
• CATATONIA : Purposeless abnormal motor activity or aggressive
behavior
Cognitive Symptoms
• POOR EXECUTIVE FUNCTIONING : Unability to understand information
to make decisions
• POOR WORKING MEMORY : Unability to use information immediately
after learning 10

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Negative Symptoms
• FLAT EFFECT : Reduced expression of emotions via facial expression or
voice tone
• ALOGIA : Reduced speech
• AVOLITION : Inability to begin & sustain activities
• ANHEDONIA : Inability to experience pleasure
• ASOCIALITY : Withdrawal from social contacts
• Reluctance to perform everyday tasks

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13. PATHOPHYSIOLOGY
1. Dopamine Hypothesis
• Numerous Positron Emission Tomography (PET) studies have shown
dopaminergic hyperactivity in the nucleus accumbens and dopaminergic
hypofunction in the fronto temporal regions.
• PET studies using D2-specific ligands provide data suggesting increased
densities of D2 receptors in the nucleus accumbens.
• PET studies assessing D1 function suggest that subpopulations of
schizophrenics may have decreased densities of D1 receptors in the
prefrontal cortex.
• Thus positive symptoms are thought to result from overactivity in the
mesolimbic dopaminergic pathway activating D2 receptors whereas
negative symptoms may result from a decreased activity in the
mesocortical dopaminergic pathway where D1 receptors predominate.
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15. 15
Dopamine Tract Origin Innervation Function
Nigrostriatal Substania niagra Striatum Movement
Mesolimbic
Ventral
tragmentum
(area of mid
brain)
Nucleus Accumbens
and Amyglada (area
of lymbic system)
Arousal, stimulus
processing,
motivational
behavior
Mesocortical
Ventral
tragmentum
Frontal and
Prefrontal Lobe
Cortex
Cognition,
communication,
social function,
response to stress
Tuberohypophyseal
or
Tuberinfundibular
Hypothalamus Pituitary gland
Inhibit prolactin
release

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2. Glutamate Hypothesis
• NMDA receptor hypofunction is thought to reduce the level of activity in
mesocortical dopaminergic neurons. This would result in a decrease in
dopamine release in the prefrontal cortex and thus give rise to negative
symptoms of schizophrenia.
• On the other hand, NMDA receptor hypofunction
is thought to enhance activity in the mesolimbic
dopaminergic pathway, perhaps because in this
pathway the important NMDA receptors are those
located on GABAergic interneurons.
• Thus NMDA receptor hypofunction would result
in reduced GABAergic inhibition (disinhibition)
of mesolimbic dopaminergic neurons and thus
give rise to enhanced dopamine release in limbic
areas such as the nucleus accumbens.

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3. 5-HT Hypothesis
• Serotoninergic receptors are present on dopaminergic axons and it is
known that stimulation of these receptors will decrease DA release in
prefrontal cortex.
• Patients with schizophrenia with abnormal brain scans have higher whole
blood 5-HT concentrations and these concentrations are correlated with
increased ventricular size.
• Atypical antipsychotics with potent 5-HT2 receptor antagonist effects
reverse worsening of symptomatology induced by 5-HT agonists in
patients with schizophrenia.

19. COMPLICATION
1. DEPRESSION : Depression afflicts approximately half of schizophrenic
patients. Sadly, it is not always recognized or treated. It can significantly
add to the suffering of the person. Additionally, comorbid depression
increases the risk of suicide in schizophrenic.
2. ANXIETY : Many individuals with schizophrenia also have an anxiety
disorder, such as social anxiety disorder, PTSD, generalized anxiety
disorder, OCD or panic disorder. In fact, research suggests between
30% and 85% of people with schizophrenia have had
an anxiety disorder at some point in time.
3. SUICIDE : Suicide is one of the primary causes of death for individuals
with schizophrenia. There are several factors which contribute to
suicide risk in schizophrenia which include psychotic symptoms, such
as voices telling the person to kill himself, substance abuse, recent
diagnosis of schizophrenia and comorbid depression.
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4. SUBSTANCE ABUSE & SMOKING : Substance abuse is a form of
self-medication for many people with psychiatric disorders.
Unfortunately, when patients use substances such as alcohol or street
drugs it can make their symptoms worse. They are also less likely to
continue taking their medications when they abuse substances.
5. VIOLENCE : While the media often depicts schizophrenic patients as
violent, they are not necessarily more prone to violence than the
general population. That being said, some factors can increase the risk
of violent behavior in individuals with schizophrenia, such
as delusions or command hallucinations, a history or violent acts or
using alcohol or drugs.
6. SELF-INJURY : Self-injury, especially bizarre types of self-mutilation, is
not uncommon with schizophrenia. Hallucinations and delusions can
cause them to harm themselves in ways which can be very serious,
such as attempting to remove a finger or other body part.

21. DIAGNOSIS
• DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA : It includes the criteria
in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),
published by the American Psychiatric Association.
• MEDICAL HISTORY : A thorough medical history is the first step in the
diagnosis of schizophrenia. This may be done to find other problems that
could be causing symptoms and to check for any related complications.
• BLOOD TESTS & IMAGING : A Complete Blood Count (CBC) test is
helpful to monitor general health and rule out other conditions that may
have been responsible for the symptoms. A blood test can provide
accurate information about the involvement of recreational drugs. In
some cases, certain imaging techniques such as Magnetic Resonance
Imaging (MRI) or Computed Tomography (CT) scan may aid in the
diagnosis.
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• PSYCHIATRIC EVALUATION : A doctor or mental health professional
checks mental status by observing appearance, demeanor and asking
about thoughts, moods and awareness. A person may be diagnosed if
they have at least 2 of the following symptoms usually over a month :
• Delusions
• Hallucinations
• Disorganised behaviour
• Disorganised speech and thought processes
• Catatonic behaviour, presenting as strong daze or hyperactivity
• Negative symptoms, impaired normal function

23. PROGNOSIS
• There is no known cure for Schizophrenia. Fortunately, there are effective
treatments that can reduce symptoms, decrease the likelihood that new
episodes of psychosis will occur, shorten the duration of psychotic
episodes, and in general, offer the majority of people the possibility of
living more productive and satisfying lives.
• With the proper medications and supportive counseling, the ability of
schizophrenic persons to live and function relatively well in society is
excellent.
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24. MANAGEMENT
HOSPITALIZATION
• During crisis periods or times of severe symptoms, hospitalization may be
necessary to ensure safety, proper nutrition, adequate sleep and basic
hygiene.
PSYCHOSOCIAL INTERVENTIONS
• Individual therapy : Psychotherapy may help to normalize thought patterns.
Also, learning to cope with stress and identify early warning signs of relapse can
help people to manage their illness.
• Social skills training : This focuses on improving communication, social
interactions and improving the ability to participate in daily activities.
• Family therapy : This provides support and education to patient families.
• Vocational rehabilitation and supported employment : This focuses on
helping people with schizophrenia prepare for, find and keep jobs.
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ELECTROCONVULSIVE THERAPY
• For adults with schizophrenia who do not respond to drug therapy,
electroconvulsive therapy (ECT) may be considered. ECT may be helpful
for someone who also has depression.
• The indications for ECT in schizophrenia are :
• Catatonic stupor & uncontrolled catatonic excitement
• Acute exacerbations not controlled with drugs
• Risk of suicide, homicide or danger of physical assault
COGNITIVE BEHAVIOURAL THERAPY
• CBT aims to help to identify the thinking patterns that are causing to have
unwanted feelings & behavior and learn to replace this thinking with more
realistic and useful thoughts.
• Most people require between 8 and 20 sessions of CBT over the space
of 6 to 12 months. CBT sessions usually last for about an hour.

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CLINICAL MANAGEMENT
• The APA guidelines treatment recommendations for patient with
schizophrenia divide the treatment into 3 phases :
1. Acute Phase (Initial Presentation) 4 to 8 weeks : Defined by acute
psychotic episode
2. Stabilization Phase (Early symptom remission) as long as 3 months
: Constitutes a time – limited transition to continuing treatment
3. Stable Phase (Maintenance treatment) : Involves stable treatment
• APA guideline refers to the American Psychiatric Association.

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28. ANTIPSYCHOTIC / NEUROLEPTIC / ATARACTIC/
MAJOR TRANQUILLIZER
Typical or Classical or 1st generation antipsychotics:
A. Phenoziazins:
1. With aliphatic amine side chain : Chlorpromazine,
Triflupromazine
2. With Piperidine side chain : Thioridazine
3. With Piperazine side chain : Trifluoperazine, Fluphenazine
B. Butyrophenones : Haloperidol, Trifluperidol, Penfluridol
C. Thiohaxanes : Flupenthixol, Thiothixene
D. Other heterocyclics : Pimozide, Loxapine
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Atypical or Novel or 2nd generation antipschycotics :
• Clozapine
• Olanzapine
• Quetiapine
• Aripiprazole
• Risperidone
• Amisulpride
• Ziprasidone

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Teatment algorithm

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• FGA – First Generation Antipsychotic
SGA – Second Generation Antipsychotic
ECT – Electro Convulsive Therapy
• Stage 1 of the treatment algorithm applies only to those patients
experiencing their first episode of schizophrenia.
• Stage 2 recommends either FGAs or SGAs, with the exception of
clozapine. Because of safety concerns and the need for white blood cell
(WBC) monitoring, it is recommended that patients be tried on one newer
SGA and one other SGA or FGA as monotherapy before proceeding to a
trial of clozapine.
• Clozapine has superior efficacy in decreasing suicidal behavior, and it
should also be considered as a higher treatment option in the suicidal
patient (Stage 3). Clozapine can also be considered earlier in treatment
in patients with a history of violence or comorbid substance abuse.

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• Stage 4 of the treatment algorithm includes clozapine and augmentation
with either a FGA, SGA, or electroconvulsive therapy (ECT). Combination
treatment at this stage is supported by limited controlled and equivocal
evidence.
• In general, patients who experience poor improvement with clozapine do
not respond well with other antipsychotic monotherapies (Stage 5).
• Stage 6 combination pharmacotherapy interventions should be
implemented with time limited, careful evaluation of a patient’s symptom
response and discontinuation of the combination if improvement does not
occur.
• If partial or poor adherence contributes to inadequate clinical
improvement, then long-acting or depot injectable antipsychotics should
be considered.
• Risperidone microspheres is the only available long-acting injectable
SGA, and long-acting FGAs include fluphenazine decanoate and
haloperidol decanoate.

33. TYPICAL ANTIPSYCHOTIC
• All anti psychotics (except clozapine-like atypical) have potent dopamine
D2 receptor blocking action.
• Antipsychotic action of typical neuroleptic is believed to produced by
competitive blockade of postsynaptic D2 receptors in mesolimbic system.
• Initially D2 presynaptic receptors are also blocked, which increases,
synthesis and release of dopamine, so its metabolites like HVA and
DOPAC level is increase in blood and urine.
• But on prolonged use, there is a feedback inhibition of DA release, due to
increased DA concentration in synaptic cleft, which result in decrease
turnover and release.
• Atypical neuroleptics drug also block D2 receptor in nigrostriatal pathway
and explain the unwanted exrapyramidal side effects (EPS).
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• Blockage of D2 receptor in CTZ is responsible for antiemetic effects.
• Neuroleptics consistently increase prolactin release by blocking the
inhibitory action of DA on pituitary lactotropes. This may result in
galactorrhoea and gynaecomastia
• Typical antipsychotic drugs Have varying degree of other receptor
blocking activity :
Clorpromazine : α1 = 5-HT2 > D2 = D4 > D1 > M1
Thioridazine : α1 > D2 > M1 = 5-HT2 > D1
Haloperidole : D2 > α1 > D4 > 5-HT2 > D1
Primozide : D2 > 5-HT2 > D4
• These drugs produce hypotension due to high α blocking property.
• Chlorpromazine potent a local anaesthetic as procaine but is not used for
this purpose because irritant action.

35. ATYPICAL ANTIPSYCHOTIC
• These newer atypical antipsychotic medications are general preffered
because they pose a lower risk of serious adverse effects than do typical
antipsychotics.
• These drugs have a moderate to high D2 antagonism and high 5-HT2A
antagonism. Clozapine have low D2 antagonism and high 5-HT2A
antagonism.
• Exception of aripiprazole, all atypical antipsychotics have higher 5-HT2A
antagonism than D2 receptor antagonism.
• Blockade of 5-HT2A receptor leads to release of dopamine in prefrontal
cortex responsible for decrease in negative symptoms while modest D2
receptor blockade in limbic system responsible for decrease in positive
symptoms.
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• At least 60% to 65% occupation of D2 receptors antagonism is necessary
to decrease positive antipsychotic symptoms, whereas 77% or more
blockade is associated with extrapyramidal side effects.
• One of the most common adverse effects of newer antipsychotics is
weight gain.
• Other adverse effects include sedation and diabetes.
• Atypical antipsychotic drugs have varying degree of other receptors
blocking activity :
• Clozapine : D4 = α1 ˃ 5-HT2 = M ˃ D2 = D1 = α2
• Quetiepine : 5-HT2 = D2 = α1 = α2
• Risperidone : 5-HT2 ˃˃ α1 ˃ H1 ≥ D2 ˃ α2 ˃˃ D1
• Olanzepine
• Aripiprazole

37. Drug
D2 binding
5-HT2A
binding
Sedation EPS
Anti-
cholinergic
Prolactin
Low
dose
High
dose
Typical
antipsychotics
70-90% ++++ +++ +++ +++
Clozapine 38-47% 38-47% 100% ++++ + +++ +
Riserpidone 60-79% 77%
70% (low)
100% (high)
+ ++ + ++++
Olanzapine 71-80% 83-88% 100% ++ + ++ +
Quetiapin 0-20% 30% 45-90% + + + +
Aripiprazole + + + +
+ low ++ moderate +++ moderately high ++++ very high 37

38. ADVERSE EFFECTS
1. SEDATION
• Although sedation is most commonly associated with chlorpromazine and
clozapine, it is primarily related to dosage with other antipsychotics.
2. AUTONOMIC SIDE EFFECTS
• Some antipsychotic drugs are associated with changes to the QT interval
measured on the elecrocardiogram (ECG) and, if given in high doses,
may increase the risk of sudden cardiac death due to α adrenergic
blockage.
• Anticholinergic side effects such as dry mouth, constipation, blurred
vision are particularly associated with piperidine phenothiazines.
• Postural hypotension, palpitation, inhibition of ejaculation and
photosensitivity are associated with the aliphatic phenothiazines.
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3. EXTRAPYRAMIDAL SIDE EFFECTS
• Side effects such as akathisia, dystonia, parkinsonian effects and tardive
dyskinesia are associated with typical antipsychotic drugs and occur
frequently, particularly with piperazine phenothiazines such as
trifluoperazine, fluphenazine and butyrophenones such as haloperidol.
Akathisia
• It is defined as the inability to sit and being functionally motor restless. It
is characterized by restlessness, convulsions, feeling of discomfort
uncontrollable & without any anxiety. The use of non-selective β blocker
can provide relief.
Dystonia
• It is a state of abnormal tonicity, sometimes described as a severe
“muscle spasm”, characterized spasm of muscles of tongue, face neck
and back; Pharangeal laranreal dystonia is life threatening. Treatment
can be made by using benzodiazepine and anticholinergic drug.

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Puedoparkinsonism
• It results due to blockadge of D2 receptor in nigrostratial pathway.
• With typical manifestations rigidity, tremor, hypokinesia, , mask-like
facial expression, micrographia, slowed speech, postural imbalance
and decreased arms wing; between 1-4 weeks of therapy and persists
unless dose is reduced.
• Treatment involve restoration of cholinergic doapaminergic balance by
using centrally acting antimuscarinic drugs like trihexyphenidyl,
procyclidin, biperiden and dopamine agonist.
Tardive Dyskinesia
• It is a syndrome characterized by abnormal involuntary movements
occurring late in onset in relation to initiation of antipsychotic therapy.
• The classic description is the buccal-lingual-masticatory (BLM)
syndrome, or orofacial movements causing involuntary facial tics or
random uncontrolled muscle movements of the hands, feet, limbs trunk.

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4. NEUROLEPTIC MALIGNANT SYNDROME (NMS)
• The NMS is a rare but serious complication of antipsychotic drug
treatment. The primary symptoms are rigidity, fever, diaphoresis,
confusion and fluctuating consciousness.
• Confirmation can be sought through detection of elevated levels of
creatinine kinase.
• The onset is particularly associated with high-potency typical drugs such
as haloperidol, recent and rapid changes to dose and abrupt withdrawal
of anticholinergic drugs.
• Treatment usually requires admission to a medical ward and withdrawal
of all antipsychotic drugs. Intravenous dantrolene may benefit as skeletal
muscle relaxant. The Dopamine agonist Bromocriptine in large doses has
been found useful to reduce rigidity and fever.

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5. HORMONAL EFFECTS AND SEXUAL DYSFUNCTION
• Blockade of D2 receptor in pituitary gland results into the effect on
prolactin. This may result in galactorrhoea, missed menstrual periods,
loss of libido in female and gynaecomasia in male.
• Some studies have suggested very high levels of sexual dysfunction with
some antipsychotic drugs such as risperidone and amisulpride.
• These drug also inhibit FSH and LH release results in amenorrhoea and
inhibition of ovulation.
6. MISCELLANEOUS
• Weight gain
• Jaundice
• Photosensitivity

43. CLOZAPINE
• The first of the new generation, clozapine is the only drug that has been
shown to be effective where other antipsychotics have failed.
• Clozapine was developed as an antipsychotic drug during the 1960s.
• It is the drug of choice for treatment resistant schizophrenia.
• It has only weak D2 blocking activity.
• Selectivity of receptor are:
5-HT2>H1=M1>α1=D4>D2=D1
ADVERSE EFFECTS
• Produce no or few extrapyramidal symptoms.
• Major side effect is agranulocytosis.
• Other side effects are sedation, unstable BP, tachycardia, urinary
incontinence, weight gain and precipitation of diabetes. 43

44. USE
• It decreases hallucination and helps to prevent suicide in people who are
likely to try to harm themselves.
• It helps to think more clearly and positively and take part in everyday life.
PHARMACOKINETIC
• Metabolized in liver by CYP34A with average half-life 12 hours.
• Bioavailability is 60 to 70%
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46. DRUG INTERACTION
1. Chlorpromazine + Propranolol Increase
plasma concentration of chlorpromazine
2. Haloperidol / Risperidone / Olanzepine + Carbamazepine
Accelerates the metabolism of antipsychotic drug
3. Phenothiazine + TCA (Tricyclic Antidepressants)
Increased antimuscarinic effects such as dry mouth and blurred
vision
4. Clozapine + SSRI (Selective Seretonin Receptor Inhibitor)
Increase plasma concentration of clozapine
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47. CONCLUSION
If you talk to God,
You are praying;
If God talks to you,
You have Schizophrenia
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