SCHIZOPHRENIA

DR. WAIRIMU KARAIHIRA

MPHARM CLINICAL PHARMACY
INTRODUCTION
 Psychotic disorders are defined by abnormalities in one or more of the
following:
 Delusions
 Hallucinations
 Disordered thinking and speech
 Grossly disorganised or abnormal motor behaviour (including catatonia)
 Negative symptoms

 Some references classify them as positive symptoms (hallucinations,

delusions and disorganised speech and behaviour), negative symptoms
(decrease in emotional range, poverty of speech, loss of interest and
drive), cognitive symptoms (deficits in memory and attention) and mood
symptoms (sadness and depression).
INTRODUCTION
Psychotic disorders include
 Schizophrenia
 Schizophreniform disorder
 Schizoaffective disorder
 Schizotypal (personality) disorder
 Delusional disorder
 Brief psychotic disorder
 Substance/Medication-induced psychotic disorder
DELUSIONS
 These are fixed beliefs that are not amenable to change in
light of conflicting evidence.
 Persecutory delusions – belief that one is being harmed or harassed
 Referential delusions – beliefs that certain gestures, comments,
environmental cues etc are directed at them
 Grandiose delusions (delusions of grandeur) – beliefs that one has
exceptional abilities, wealth or fame
 Erotomanic delusions – belief that another person is in love with him or
her
 Nihilistic delusions – belief that a major catastrophe will occur
 Somatic delusions – preoccupations regarding health and organ function
 A delusion may be bizarre is it is implausible or impossible and not
understandable to same-culture peers and does not derive from ordinary
life experiences.
HALLUCINATIONS
 These are perception-like experiences that occur without an
external stimulus.
 They are vivid and clear and not usually under voluntary control.
 The most common are auditory hallucinations usually
experienced as voices that are distinct from an individual’s own
thoughts.
 Hallucinations are only considered when one is awake.
 Delusions and hallucinations are known as positive symptoms
DISORGANISED THINKING
(SPEECH)
 Disorganised thinking is inferred from an
individual’s speech.
 An individual may switch from one topic to another,
answers to questions may be obliquely related or
unrelated.
 Speech may be incomprehensible and resemble
receptive aphasia (word salad).
 It often impairs effective communication.
DISORGANISED OR ABNORMAL
MOTOR BEHAVIOUR
This manifests from childlike “silliness” to
unpredictable agitation.
Some patients may have catatonic behaviour,
which is a marked decrease in reactivity to the
environment.
Examples include resistance to instructions and
lack of verbal and motor response
NEGATIVE SYMPTOMS
 Negative symptoms prominent in schizophrenia are
 Diminished emotional expression: reduction in the
expression of emotions on the face, reduced eye contact,
flat speech and reduced hand, head and face movement
usually used in speech.
 Avolition: decrease in motivated self-initiated purposeful
activities.
 Alogia: diminished speech output
 Anhedonia: decreased ability to express pleasure
 Asociality: lack of interest in social interactions
SCHIZOPHRENIA
EPIDEMIOLOGY AND RISK
FACTORS
 It affects 0.5-1% of the population.
 There is a strong familial association and genetic determinants.
 Schizophrenia typically occurs in late adolescence or early
adulthood. It rarely occurs in midlife, and if it does it
overwhelmingly affects women, usually presenting with
prominent paranoid symptoms.
 Incidence of schizophrenia and related disorders is higher for
children growing up in an urban environment.
 Other associations include birth during cold seasons, maternal
malnutrition, pre-natal viral exposure, stress, maternal diabetes.
PATHOPHYSIOLOGY
 Some hypotheses have been used to explain the
development of schizophrenia.
 These hypotheses are:
 Serotonin hypothesis
 Dopamine hypothesis
 Glutamate hypothesis
 Disconnect hypothesis
SEROTONIN HYPOTHESIS
 5-HT2A and 5-HT2C receptors were discovered to play a role in the
development of hallucinations following the ingestion of LSD and
mescaline.
 5-HT2A blockade is a key factor in the MOA of atypical antipsychotics.
Binding of these drugs results in the modulation of release of other
neurotransmitters in the cortex, limbic system and striatum.
 Stimulation of 5-HT2A receptors leads to depolarisation of glutamate
neurons and stabilisation of the NMDA receptors.
 Stimulation of 5-HT2C receptors modulates cortical and limbic
dopaminergic activity.
DOPAMINE HYPOTHESIS
 Evidence supporting the dopamine hypothesis are:
 Many antipsychotics block postsynaptic D2 receptors in the CNS
 Drugs that increase dopaminergic activity either aggravate schizophrenia psychosis or
produce psychosis
 Dopamine receptor density has been found to be increased in brains of untreated
schizophrenics on post-mortem
 The dopamine hypothesis attributes the positive symptoms to excessive
activation of D2 receptors in the mesolimbic pathways.
 Low levels of dopamine in the nigro-striatrial pathway cause motor symptoms
through their effect on the extrapyramidal system.
 Low levels of dopamine in the meso-cortical pathways cause the negative
symptoms
GLUTAMATE HYPOTHESIS
PCP and ketamine are non-competitive
inhibitors of the NMDA receptor that
exacerbate both cognitive impairment and
psychosis in patients with schizophrenia,
as well as increased motor activity.
DISCONNECT HYPOTHESIS
Focuses on the neuroanatomical changes seen
on PET and fMRI scans.
There is a reduction in grey matter volume in
schizophrenia, particularly in the temporal and
parietal lobes.
There are also differences in the frontal lobes and
hippocampus, contributing to a range of cognitive
and memory impairment.
CLASSIFICATION
 Paranoid schizophrenia
 Hebephrenic schizophrenia
 Catatonic schizophrenia
 Undifferentiated schizophrenia
 Post-schizophrenic depression
 Residual schizophrenia
 Simple schizophrenia
DIAGNOSTIC CRITERIA
(DSM-V)
A. Two or more of the following, each present for a significant portion of time during a 1-
month period (or less if successfully treated). At least of these must be any of the first
three:
1. Delusions
2. Hallucinations
3. Disorganised speech
4. Grossly disorganised or catatonic behaviour
5. Negative symptoms
B. For a significant portion of the time since the onset of the disturbance, level of
functioning in one or more major areas, such as work, interpersonal relations, or self-
care, is markedly below the level achieved prior to the onset (or when the onset is in
childhood or adolescence, there is failure to achieve expected level of interpersonal,
academic, or occupational functioning.
DIAGNOSTIC CRITERIA
(DSM-V)
C. Continuous signs of the disturbance persist for at least 6 months.
This 6-month period must include at least 1 month of symptoms (or less if
successfully treated) that meet Criterion A (i.e., active-phase symptoms)
and may include periods of prodromal or residual symptoms. During these
prodromal or residual periods, the signs of the disturbance may be
manifested by only negative symptoms or by two or more symptoms listed
in Criterion A present in an attenuated form (e.g., odd beliefs, unusual
perceptual experiences).
D. Schizoaffective disorder and depressive or bipolar disorder with
psychotic features have been ruled out because either 1) no major
depressive or manic episodes have occurred concurrently with the active-
phase symptoms, or 2) if mood episodes have occurred during active-
phase symptoms, they have been present for a minority of the total duration
of the active and residual periods of the illness.
DIAGNOSTIC CRITERIA
(DSM-V)
E. The disturbance is not attributable to the physiological
effects of a substance (e.g., a drug of abuse, a
medication) or another medical condition.
F. If there is a history of autism spectrum disorder or a
communication disorder of childhood onset, the additional
diagnosis of schizophrenia is made only if prominent
delusions or hallucinations, in addition to the other
required symptoms of schizophrenia, are also present for
at least 1 month (or less if successfully treated).
INVESTIGATION AND
DIAGNOSIS
 History taking
 Onset of episodes
 Past medical history
 Drug history e.g. corticosteroids
 Family history of psychiatric conditions
 Social history including the use of recreational drugs and alcohol
 Any recent neurological impairments such as altered consciousness,
memory problems, head injury, stroke, seizures, fainting, dizziness, visual
impairment, tremor or muscle stiffness
 Potential organic causes of psychosis such as Parkinson’s disease, multiple
sclerosis, syphilis, AIDS, brain tumour, heavy metal toxicity, delirium,
endocrine disorders or dementia
INVESTIGATION AND
DIAGNOSIS
 Some lab and imaging tests may be conducted to rule out other potential
causes of psychosis
 UECs
 Serum calcium and PTH- hypo or hyperparathyroidisim may have psychiatric
manifestations
 Blood glucose – hypoglycaemia may produce confusion which can be
mistaken for psychosis
 TFTs- depression associated with hypothyroidism may present with psychotic
features
 24-h cortisol urine collection- both Cushing’s syndrome and Addison’s
disease may present with psychiatric features
INVESTIGATION AND
DIAGNOSIS
 24-h catecholamine/5-Hydroxyindoleacetic acid
(HIAA) collection in suspected cases of
phaeochromocytoma or carcinoid syndrome.
 Toxicology screening
 CT/MRI of the head- in case of severe neurological
impairment
 HIV/syphilis testing
INVESTIGATION AND
DIAGNOSIS
Screening tests
Criteria for Prodromal syndromes (COPS)
Structured Interview for Prodromal
Syndromes (SIPS)
Personal Assessment and Crisis
Evaluation Clinic (PACE)
 ANTIPSYCHOTIC AGENTS
 Antipsychotic agents are conventionally divided into two classes:
Typical (First-generation) and Atypical (Second generation).
 First generation antipsychotics include Chlorpromazine, Haloperidol,
Zuclopenthixol and Fluphenazine.
 Second generation antipsychotics include Aripiprazole, Clozapine,
Olanzapine, Quetiapine and Risperidone.
 The major difference between the two classes is that the typical
antipsychotics have a higher likelihood of causing extrapyramidal
side effects (akinesia, dystonia). Second generation antipsychotics
have a higher risk of metabolic ADRs such as weight gain, diabetes
and hypercholesterolemia.
ANTIPSYCHOTIC AGENTS
 All typical antipsychotics exert their action through dopamine blockage
(D2 receptors).
 Chlorpromazine

 Most atypical antipsychotics have D2 blockade as well as inhibition of

serotonin receptors
 Clozapine has a high affinity for D1, D4, 5-HT2, muscarinic and alpha
adrenergic receptor
 Risperidone and Olanzapine block 5-HT2A receptors to a greater extent than D2
receptors
 Aripiprazole is a partial agonist at D2 and 5-HT1A receptors as well as
antagonist at 5-HT2A receptors.
 Quetiapine is relatively weak at its blockade to the D2 and 5-HT2A receptors.
ADRS OF ANTIPSYCHOTIC
AGENTS
Adverse effects are primarily due to their ability
to bind to multiple receptors.
 Dopamine
 Serotonin
 Norepinephrine
 Alpha adrenergic
 Muscarinic
 Histamine
ADRS OF ANTIPSYCHOTIC
AGENTS: EPS
 Extrapyramidal effects are due to blockade of
dopamine receptors in the nigrostriatal pathway.
 They include
 Dystonias (twitching, distorted postures). Acute dystonia
may be managed using an antihistamine with
anticholinergic activity e.g. diphenhydramine
 Parkinson-like symptoms (tremor, rigidity,
bradykinesia). Parkinsonism may be treated with
antimuscarinic antiparkinsonian agents, lowering the
dose of the antipsychotic or switching to another
medication
ADRS OF ANTIPSYCHOTIC
AGENTS: EPS
 They include
 Akathisia (motor restlessness). Akathisia may be
managed by lowering the dose of the antipsychotic,
switching, adding a benzodiazepine or a beta blocker.
 Tardive dyskinesia (a chronic ADR of antipsychotic use
that presents with involuntary movements of the tongue,
lips, neck, trunk and limbs). Tardive dyskinesia may be
managed by withdrawing the culprit and replacing with
clozapine or quetiapine, withdrawing all drugs with
anticholinergic activity and finally diazepam (increased
GABAergic activity).
 https://www.youtube.com/watch?v=7odlzmF6F5s
ANTIPSYCHOTIC AGENTS
2. Lowering of the seizure threshold
3. Anticholinergic effects such as dry mouth (except clozapine that increases
salivation), blurred vision, confusion, constipation and urinary retention.
4, Alpha adrenergic blockade causes orthostatic hypotension and light-
headedness.
5. Sedation due to H1 receptor inhibition particularly with chlorpromazine,
olanzapine, quetiapine and clozapine.
6. Sexual dysfunction
7. Metabolic and endocrine disturbances such as weight gain, hyperglycaemia
and hyperlipidemia is mainly seen with olanzapine and clozapine.
8. Hyperprolactinaemia due to dopamine inhibition may result in osteoporosis
(in women) amenorrhoea, galactorrhoea, infertility and loss of libido.
ANTIPSYCHOTIC AGENTS
9. Agranulocytosis is seen with clozapine. Patients should have weekly
blood counts for the first 6 months of treatment then every 3 weeks
thereafter
10. Phenothiazines may cause visual disturbances because of deposits
in the cornea and lens.
11. QT prolongation may be seen with thioridazone, ziprasidone and
iloperidone.
12. Neuroleptic malignant syndrome is a life-threatening complication of
antipsychotics.
 It is characterised by muscle rigidity, fever, altered mental status, stupor, unstable
blood pressure and myoglobinemia.
 Treatment includes the withdrawal of antipsychotics, administration of
bromocriptine, dantrolene or diazepam. Cooling of the patient.
GOALS OF THERAPY
Reduce acute symptoms
Prevent the recurrence of symptoms
Maximise functioning and quality of life
PHARMACOLOGICAL
MANAGEMENT
 Antipsychotic agents diminish the positive symptoms and prevent but rarely have an
effect on the negative symptoms.
 These drugs are more or less equivalent in their effectiveness, save for clozapine
which appears to outperform all of them,
 The choice of initial antipsychotic therapy is dependent on
 Effectiveness
 Cost
 Side effect burden
 Method of delivery
 Availability
 Tolerability
 Ability of the patient to comply with medication
PHARMACOLOGICAL
MANAGEMENT
 If the patient does not respond to a medication, their healthcare team can opt for
adding another medication, switching to another medication or increasing the dose.
 A long acting injectable agent (fluphenazine decanoate, haloperidol decanoate,
risperidone microspheres, paliperidone palmitate, aripiprazole monohydrate,
aripiprazole lauroxil and olanzapine pamoate) may be used in patients with a history
of poor or uncertain adherence or if it is the patients choice
 Clozapine is the drug of choice in
 Treatment resistant schizophrenia
 Patients with a substantial risk for suicide or suicidal attempts despite other treatments
 Patients with a high risk of aggressive behaviour despite other treatments

 Patients should be monitored for adverse effects and the effects managed or
prevented e.g. benzhexol is usually used with antipsychotics to prevent EPS
PHARMACOLOGICAL
MANAGEMENT
 A benzodiazepine (eg, lorazepam) may be used
during the initiation of an antipsychotic to minimize
agitation or aggression and allow time for the
antipsychotic to take effect. For management of acute
agitation or aggression, the addition of lorazepam
may also allow lower dosages of the antipsychotic to
be used and help prevent antipsychotic-induced side
effects such as extrapyramidal symptoms (eg,
dystonia).
NON-PHARMACOLOGICAL
MANAGEMENT
 Patient education on the importance of medication compliance, avoidance of alcohol
and other drugs of abuse and recognition of the signs of decompensation e.g.
insomnia or increased irritability
 Patients with schizophrenia should be treated with Cognitive Behavioural Therapy for
Psychosis (CBTp).
 Other psychosocial interventions include Psychoeducation, Family interventions,
Vocational rehabilitation, Cognitive remediation and Social skills training.
 Electroconvulsive therapy (ECT) is reserved for refractory schizophrenia. Transcranial
magnetic stimulation (TMS) is also a potential therapy.
 Nutritional counselling and dietary modification is important as many antipsychotics
cause metabolic disturbances.
QUESTIONS
 An adolescent male is newly diagnosed with schizophrenia. Which of the following
neuroleptic agents may improve his apathy and blunted affect?
 A. Chlorpromazine.
 B. Fluphenazine.
 C. Haloperidol.
 D. Risperidone.
 E. Thioridazine.