PSY344 – Week 1


 Schizophrenia literally means ‘Fragmented Mind’ or
‘split-mind’ due to the inability to differentiate
fantasy and reality.
 Schizophrenia is considered one of the mot complex,
chronic and challening psychiatric disorders
affecting how a person thinks, feels, behaves and
severely distorts perception.
 It represents a heterogenous syndrome of
disorganized thoughts, delusions, hallucinations and
impaired psychosocial functioning.
Schizophrenia


 While many factors have been associated with
developing schizophrenia.
 These include genetics, early environment,
neurobiology and psychological and social
processes.
 An exact cause of the disease still cannot be
accounted for.
Etiology


Etiology


 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.
 Genetics:
 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%. 5
Etiology


 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 and tend to be diagnosed later in life
than men.
Epidemiology


Epidemiology


 Schizophrenia
 Schizotypal (Personality) Disorder
 Brief Psychotic Disorder
 Schizophreniform Disorder
 Schizoaffective Disorder
 Substance Induced or Due To Another Medical Condition
Types According to DSM


 Schizophrenia breaks down into 3 categories of
symptoms.
 These are as follows:
 Positive Symptoms
 Negative Symptoms
 Cognitive Deficits
Symptom Types


 Positive Symptoms refer to overt symptoms that
shouldn’t be present. These include;
 Hallucinations
 Delusions
 Disorganized Thoughts
Positive Symptoms


 Negative symptoms refer to a lack of characteristics
that should be present. These can include;
 Reduced speech even when encouraged to interact
(alogia)
 Lack of emotional and facial expressions (affective
flattening)
 Diminished ability to begin and sustain activities
(avolition)
 Decreased ability to find pleasure in everyday
activities (anhedonia)
 Social withdrawal (asocial)
Negative Symptoms


 Refers to difficulties with following aspects of
cognition that can make it hard to live a normal life
or sustain a job / living. These include deficiencies
in;
 Memory
 Attention
Cognitive Deficits


 Delusions: False beliefs that are not based on reality.
 Hallucinations: Involving seeing or hearing things
that don’t exist.
 Disorganized Speech and Thinking: Effective
communication can be impaired and answers to
questions may be partially or completely unrelated.
 Catatonia: Purposeless abnormal motor activity or
aggressive behaviour.
Positive Symptoms Examples


 Flat Effect: Reduced expression of emotions facial
expression or voice tone.
 Alogia: Reduced speech.
 Avolition: Inability to begin and sustain activities.
 Anhedonia: Inability to experience pleasure.
 Asociality: Withdrawal from social contacts.
 Reluctance to perform everyday tasks.
Negative Symptoms
Examples


 Any visible cognitive impairment can be considered
as a cognitive symptom category, the most
commonly observed are;
 Poor Execution Functioning: Inability to understand
information to make decisions.
 Poor Working Memory: Inability to use information
immediately after learning.
Cognitive Symptoms Examples


The Brain Associated with
Schizophrenia


 Dopamine Hypothesis:
 Numerous Positron Emission Tomography (PET) studies have
shown dopaminergic hyperactivity in the nucleus accumbens and
dopaminergic hypofunction in the frontal 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.
Pathophysiology


Pathophysiology


Pathophysiology


Pathophysiology


 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 GABA interneurons.
 Thus NMDA receptor hypofunction would result in reduced
GABA inhibition (disinhibition) of mesolimbic dopaminergic
neurons and thus give rise to enhanced dopamine release in
limbic areas such as the nucleus accumbens.
Pathophysiology


Pathophysiology


 5-HT (Hydroxytryptamine (Serotonin)) 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.
Pathophysiology


 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.
 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.
 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
Complications


 Substance Abuse and 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.
 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.
 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.
Complications


 Diagnostic Criteria of Schizophrenia:
 Includes the criteria in the Diagnostic and Statistical Manual of Mental
Disorders (DSM-V-TR), 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 and 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.
Diagnosis


 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
Psychiatric Evaluation


 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.
Prognosis


 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.
Management Hospitalization


 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.
Management Hospitalization


 Clinical Management:
 The APA guidelines treatment recommendations for
patient with schizophrenia divide the treatment into 3
phases:
 Acute Phase (Initial Presentation) 4 to 8 weeks:
Defined by acute psychotic episode.
 Stabilization Phase (Early symptom remission) as long as
3 months:
Constitutes a time – limited transition to continuing
treatment.
 Stable Phase (Maintenance treatment):
Involves stable treatment.
Management Hospitalization


APA Guidelines and Treatment
Goals for Schizophrenia


 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
Antipsychotics, Neuroleptic
and Major Tranquilizers


 Clozapine
 Olanzapine
 Quetiapine
 Aripiprazole
 Risperidone
 Amisulpride
 Ziprasidone
Atypical or Novel or 2nd
Generation Antipsychotics


Treatment Algorithm


 Stage 1:
 Treatment only applies only to those patients experiencing
their first episode of schizophrenia.
 Stage 2 and 3:
 Recommends either First Generation Antipsychotics or Second
Generation Antipsychotics, 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 Second Generation Antipsychotics and one other
Second Generation Antipsychotics or First Generation
Antipsychotics 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.
Treatment Algorithm


 Stage 4, 5 and 6:
 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.
Treatment Algorithm


 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).
Typical Antipsychotics


 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.
Typical Antipsychotics


 These newer atypical antipsychotic medications are
general prefered 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.
Atypical Antipsychotics


 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
Atypical Antipsychotics


Atypical Antipsychotics


 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.
Adverse Effects


 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.
Adverse Effects


 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.
Adverse Effects


 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.
Adverse Effects


 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
Adverse Effects


 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.
Clozapine


 Usage:
 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%.
Clozapine


 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
Drug Interaction