07-Jan-21

• The Basics of Psychotic Illnesses

• Group of heterogeneous conditions
Antipsychotic drugs • Multifactorial causes
• Prenatal insults
Neuroleptics • Late genetic factors
• Late environmental factors
• 3 symptom clusters
• Positive
• Negative
https://www.youtube.co
• Cognitive m/watch?v=Rws1niDxqK
8/

Schizophrenia - symptoms
Positive Symptoms(↑↑DA) Negative Symptoms(↓↓NMDA)
Hallucinations Blunted emotions Very Early Onset Psychosis
Delusions (bizarre, persecutory) Anhedonia • before 13
Disorganized Thought Lack of feeling
Perception disturbances Early Onset Psychosis
Inappropriate emotions • before 16
Schizophrenia
FUNCTION • later onset

Mood Symptoms
Cognition Loss of motivation
New Learning Social withdrawal
Memory Insight
Demoralization
Suicide

Antipsychotic Drugs:
Mechanism of Action
First Generation
• All antipsychotic drugs interact with a
• Second generation antipsychotics vary
variety of neurotransmitter systems.
First generation antipsychotics
typically block dopamine receptors
(especially D2 receptors). They reduce
positive symptoms, such as delusions,
hallucinations, formal thought
disorder, as well as other non-specific
symptoms such as agitation and
aggressiveness. They are also
associated with elevated prolactin
secretion, extrapyramidal side effects
such as tremor, dystonia and tardive
dyskinesia, and with rare but
potentially fatal side effects such as
neuroleptic malignant syndrome.
07-Jan-21
Second Generation
in their receptor affinity, targeting
mainly serotoninergic (5HT2A) as well
as D2 and other receptors . It was
believed initially that second
generation antipsychotics were
effective in reducing negative
symptoms. However, evidence of this
is inconclusive. Because
extrapyramidal symptoms can
exacerbate negative symptoms and
because second generation
antipsychotics have fewer
extrapyramidal effects, this can give
the false impression of a reduction in
negative symptoms with atypical
antipsychotics. Second generation
antipsychotics mainly cause weight
gain, dyslipidaemia, and type II
diabetes.
PHARMACOKINETICS
Most neuroleptic drugs are highly lipophilic, bind avidly to proteins, and tend to accumulate in highly
perfused tissues. Oral absorption is often incomplete and erratic, whereas IM injection is more reliable.
With repeated administration, variable accumulation occurs in body fat and possibly in brain myelin. Half-
lives are generally long, and so a single daily dose is effective. An esterified derivate of fluphenazine
requires dosing only once every few weeks. After long-term treatment and drug administration is stopped,
therapeutic effects may outlast significant blood concentrations by days or weeks. This may result from
tight binding of parent drug of active metabolites in the brain.
• Metabolism of antipsychotic drugs usually starts with oxidation by hepatic microsomal enzymes (P450
system), followed by glucuronidation and excretion in urine. After long-term use, the rate of conversion of
parent drug increases slightly, causing a mild metabolic tolerance; however, monitoring the blood
concentration of drug is generally not useful in preventing this problem. In individual patients, very wide
variations in blood concentration of antipsychotic agent can still achieve control of symptoms. Thioridazine
because of its prominent anticholinergic activity in the gastrointestinal tract, may display erratic absorption
after oral administration. Even with regular dosing, especially in older patients, periods of inadequate or
excessive blood concentrations of drug may result.
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Antipsychotic Drugs – New Generations Clozapine (1989)

“atypical” • Selectively blocks dopamine D2 receptors,
avoiding nigrostriatal pathway
• clozapine
• risperidone • α-blockade
• olanzapine • Also blocks H1
• sertindole • More strongly blocks 5-HT2 receptors in cortex
• Quetiapine which then acts to modulate some dopamine
• Aripiprazole activity
• Ziprasidone • Among non-responders to first generation meds or
those who cannot tolerate side effects, about 30%
do respond to Clozapine

Clozapine Risperidone (1994)

• Extrapyramidal side effects are minimal
• May help treat tarditive dyskinesia
• S/E- orthostatic hypotension effects, sedation, weight
gain, increased heart rate
• Increased risk for seizures (2-3%)
• Agranulocytosis in 1%
• Agranulocytosis risks increase when co-administered
with carbamazepine
• Fewer side effects than Clozapine
• Marketed as first line approach to treatment
• Blocks selective D2, norepinephrine, and 5-HT2
• effective for positive and negative symptoms
• Extrapyramidal side effects low (but are shown at
high doses)
• Shares sedation, weight gain, rapid heart beat,
orthostatic hypotension, and elevated prolactin
• No agranulocytosis risks
• Increased risk of stroke in elderly
• May cause anxiety/agitation (possible OCD)
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• Not much data for kids and teens • Treatment of 1st episode psychosis:
• Most data extrapolated from adult studies • 80 % better first antipsychotic
• 5% better with different antipsychotic
• Unclear efficacy in typical vs atypical • 15% treatment resistant
• Choice of right antipsychotic mostly trial and error • ¾ of these better on clozapine
• Most guidelines recommend atypical first • Recurrence common
• If not available, start haloperidol or chlorpromazine • Important to prevent exacerbations given major life
low and slow to minimize EPS tasks of young adulthood

Oral Formulations: Injectables:

• Clinicians are often anxious about using LAIs because of:
• Rapid discontinuation • Detection of relapse
• The belief that LAIs are associated with worse side-effects (despite lack of evidence supporting this)nConcerns regarding
patients’ acceptance of LAIs (patients on this formulation often prefer it) Apprehension regarding reduced patient
autonomy
• Enhanced autonomy • Improved Relapse
• Worries about nursing staff involvement in administering LAIs, training and time pressures on staff—so that they can
adequately and routinely monitor symptoms and side-effects • Less frequent visits prevention
•
•
Preferential attention to more fashionable medications
Lower prescriber knowledge about and experience with LAIs
• Less rehospitalization
• Cost.
EQUAL EFFICACY • Stable concentrations
• Not taking antipsychotic medication is the single largest modifiable risk factor for the recurrence of positive symptoms of
schizophrenia (Subotnik et al, 2015). • Less poisoning risk
•
•
Long-acting injectable antipsychotics (LAIs)—also known as depot antipsychotics
Developed to enhance adherence at a time of extensive psychiatric hospital de-institutionalisation of patients and the
• Efficacy vs Adherence
need for an effective community-based treatment .
• 1st= fluphenazine enanthate and decanoate were introduced in 1966.
• Clinician concerns
Reduced rehospitalisation rates
• Association with worse side effects? More stable serum concentrations
Patients’ acceptance?
•
• Reduced patient autonomy?
Reduced risk of accidental or deliberate self-poisoning
• Nursing involvement? Better ability to distinguish between lack of efficacy and poor adherence.
• Less fashionable?
• Less knowledge and experience?
• Cost?
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An acute dystonic reaction is characterized by

involuntary contractions of muscles of the extremities,
face, neck, abdomen, pelvis, or larynx in either sustained
or intermittent patterns that lead to abnormal
movements or postures.
• Not uncommon in emergency room
• Often seen in young patients
• Metoclopramide, prochlorperazine or antipsychotics
• Differential diagnosis: tetanus and strychnine
poisoning, hyperventilation, hypocalcemia,
hypomagnesemia, Wison’s Disease, catatonia

• Dystonia responds promptly to anticholinergic drugs Neuroleptic Malignant Syndrome (NMS)

(e.g., benztropine 1-2mg by slow intravenous injection)
or antihistaminics (e.g., diphenhydramine).
• Children should be given parenteral benztropine
(0.02mg/kg to a maximum of 1mg), either
intramuscularly or intravenously. Most patients respond
within 5 minutes and are symptom-free by 15 minutes
• If there is no response the dose can be repeated after 10
minutes (or 30 minutes in children if intramuscularly).
• If the dystonic reaction does not improve, the diagnosis
is probably wrong.
https://www.youtube.com/watch?v=2krwEbm5hBo
• Hyperthermia, muscular rigidity, tachycardia, hyper or
hypotension, autonomic instability, rhabdomyolysis,
confusion
• Increased creatine phosphokinase and leukocytes
• More common in first weeks of treatment
• Increased risk with higher doses, multiple drugs, male,
and young
• Can lead to loss of consciousness and death
• Misdiagnosis: catatonia, EPS, serotonin syndrome,
infectious disease
• Supportive management and stop drug
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Adverse Effects - EPS

Details on two main extrapyramidal disturbances (EPS):
Sedation
• Parkinson-like symptoms • Frequent and dose dependent
• tremor, rigidity
• direct consequence of block of nigrostriatal DA2 R • Tolerance may develop
• reversible upon cessation of antipsychotics
• May be a wanted effect in agitated patients
• Tardive dyskinesia
• involuntary movement of face and limbs • More sedating agents
• less likely with atypical antipsychotics (AP) • Chlorpromazine
• appears months or years after start of AP • Clozapine Sensitivity to sun
• ? result of proliferation of DA R in striatum • Quetiapine • some phenothiazines collect in skin
• presynaptic? (chlorpromazine)
• treatment is generally unsuccessful • sunlight causes pigmentation changes – grayish-
purple (look bruised)
•in eye, brown cornea, brownish cloud to vision and
possibly permanent impairment

Weight Gain Metabolic Syndrome Preventing Weight Gain and Metabolic Syndrome:
• Most common long term Obesity, • Goal: healthy eating, BMI<25, exercise
adverse effect of atypicals hypertriglyceridemia, • Clinically Monitor
• 5% weight gain in 1st 3 months hypertension, • Weight, waist circumference, fasting glucose/lipids
or 0.5 increase in BMI • Precursor = weight
concerning • Provide dietary and exercise advice
gain • Small, frequent, slow meals with water
• Dyslipidemia, metabolic • Insulin secretion • Reduce sugar, saturated fat, processed white flour
syndrome, diabetes mellitus, problems
hypertension, polycystic • Increase fiber, fruits, vegetables
ovary, • Especially clozapine • Exercise 30-60 minutes each day
and olanzapine
• Social withdrawal, treatment
discontinuation, self esteem
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Suggested monitoring for people taking antipsychotics

• First, define goals

• Choose atypical antipsychotic
• not clozapine or olanzapine
• Take into account:
• Side effects
• Patient’s drug response history
• Patient’s family history of drug response
• Availability
• Clinician’s familiarity
• Price

Patients having a first episode vs. multi-episode: • No consensus

• Better response to treatment • Majority agree on 4-6 weeks
• Greater likelihood of side effects • If not switch antipsychotics

• Require lower doses • ½ to 2/3 experience reduced positive symptoms in 3

• Except quetiapine (500-600mg/day) weeks at initial dose
• If not increase dose
• Start low and go slow
• If increased too quickly to too high of drug
• No increased effectiveness
• More side effects
• Poor adherence
• Poor longterm outcomes
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The reliability of diagnosis: whether there is a high or low certainty about the diagnosis of
schizophrenia
• Use in youth increasing since 1990s, esp in US
• Whether there is reasonable evidence suggesting the existence of a mood disorders (e.g.,
antipsychotic treatment may not need to be prolonged in cases of psychotic depression)
• Prescribed mainly off-label
• The duration of the psychotic episode (e.g., if it was brief, shorter than one month, or
more prolonged)
• Worrisome adverse effect burden
• The nature of the psychotic episode (e.g., a drug-induced psychosis)
• Whether complete recovery was achieved or whether symptoms, particularly negative • Prescribers often not trained in psychiatry
symptoms, persist. Most patients with the so-called chronic schizophrenia may need
lifelong medication treatment
• Other options with fewer side effects for:
• Patient’s insight and adherence to treatment (e.g., if the patient is willing to be reviewed
regularly and has a good understanding of the illness and of the initial symptoms of a • ADHD
recurrence)
• Presence of comorbid conditions such as depression or substance misuse • Disruptive behaviors
• Age at first episode (earlier onset has worse prognosis) • Depression
• Whether there have been previous episodes • Anxiety
• The life stage: it would be unwise to cease treatment during important life transitions
(e.g., starting university) or stressful periods
• Whether there are relatives or social supports who can monitor early deterioration
• Severity of side effects of medication.

• Optimally, care for patients with a first episode of psychosis should be

coordinated and individualized, provided through services that are specific • Consider inpatient hospitalization if:
for each phase of the illness (Ministry of Health, Province of British
Columbia, 2010; International Early Psychosis Association Writing Group • Youth not engaged in treatment and actively psychotic
(2005). For example, minimising in-patient hospitalization during the acute
phase should be a goal— young people often find their initial inpatient  May necessitate involuntary hospitalization
experience traumatizing (McGorry et al, 1991). Treatment should be
provided in an outpatient setting or the home when possible. Ways to avoid • Significant risk to self or others
hospitalization include: • Insufficient community support
• Increasing the number of outpatient visits • Crisis too severe to manage
• If available, outreach treatment team follow-up
• Access to emergency services when required, and
• Supported housing or residential care.

• The level of intervention (inpatient, outpatient) depends largely on the

degree of family, community and health services support rather than on the
degree of psychopathology itself. Acute day-stay services and early
intervention programs may be appropriate alternatives to in-patient care.