Regina HJ Lee Schizophrenia NS

Schizophrenia
Antipsychotics/Neuroleptics/Anti-schizophrenics/Major Tranquilisers
Psychotic illness include various disorders, but the term antipsychotic drugs conventionally refer to
those used to treat Schizophrenia. (These same drugs are used to treat mania and other acute
behavioural disturbances).
FACTS ABOUT SCHIZOPHRENIA

Schizophrenia: A long-term mental disorder of a type involving a breakdown in the relation between thought,
emotion, and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from
reality, personal relationships into fantasy and delusion, and a sense of mental fragmentation.

Schizophrenia affects about 1% of the population and 1 in 100 people during their lifetime.
Low incidence (new cases coming out) but high prevalence (number of people who suffer).
Gender incidence is equal.
The disease, starting between ages 15 and 35 (later onset for women), is one of the most important
forms of psychiatric illness because it affects young people, is often chronic and is highly disabling.
There is a strong hereditary (inheritance) factor in its aetiology, and evidence suggestive of a
fundamental biological disorder.
Myths – associated with violence / hospital admission required. Many people with Schizophrenia live
a stable life, work and have relationships.
SYMPTOMS
Positive (Type 1)
1. Catatonia (immobility or purposeless motor activity).
2. Abnormal, disorganised behaviour (stereotyped movements – physical movements that are
aimless and repetitive, disorientation and occasionally aggressive behaviour).
3. Thought disorder (comprising wild trains of thought, delusions of grandeur, garbled sentences
and irrational conclusions) and Thought Broadcasting (others can hear my thoughts).
4. Hallucinations (often in the form of voices - which may be exhortatory in their message - but
also smelling/seeing/feeling).
5. Delusions (often paranoid in nature).
6. Feeling of being controlled (thoughts vanishing/thoughts not your own/body is being taken over
and controlled by someone else).
Negative (Type 2)
1. Flattening of emotional responses.
2. Anhedonia (inability to experience pleasure).
3. Reluctance to perform everyday tasks.
4. Social withdrawal.
5. Self-Neglect (not washing/tidying).
6. Affective Blunting (not interested in friends or family).
Neurocognitive Impairment
1. Deficits in cognitive function (eg, attention, memory).

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2. Executive function (eg, doing tasks, planning).

In addition:
1. Self-punishment.
2. Anxiety.
3. Depression.
4. Guilt.
The symptoms become more prominent with age and time (progressive, not stationary).
This leads to suicide attempts in up to 50% of cases, about 10% of which are successful.
A characteristic feature of Schizophrenia is “SELECTIVE ATTENTION”. Whereas a normal
individual quickly accommodates to stimuli of a familiar or inconsequential nature, and responds only
to stimuli that are unexpected or significant, the ability of Schizophrenic patients to discriminate
between significant and insignificant stimuli seems to be impaired.
For example, the ticking of a clock may command as much attention as the words of a companion. Or
a chance thought, which a normal person would dismiss as inconsequential, may become an
irresistible imperative (essential or urgent thing).
The clinical phenotype (observed symptoms) varies greatly, particularly with the respect to the
balance between positive and negative symptoms, and this may have a bearing on the efficacy of
antipsychotic drugs in individual cases.

 Schizophrenia in young people tends to present with predominantly positive features.

 In older patients it tends to present with negative features.
Bear in mind that NOT ALL SYMPTOMS need to be treated – have to consider which will affect
society if left untreated.
Acute or Chronic
Schizophrenia can follow a relapsing and remitting course, or be chronic and progressive,
particularly in cases with a later onset.
Acute episodes (mainly positive symptoms) frequently recur and may develop into chronic
Schizophrenia, with predominantly negative symptoms.
Chronic Schizophrenia used to account for most of the patients in long-stay psychiatric hospitals.
Following the closure of many of these in the UK, it now accounts for many of society’s outcasts.
AETIOLOGY AND PATHOGENESIS OF SCHIZOPHRENIA
The causes of Schizophrenia remain unclear but involve a combination of genetic and environmental
factors. Thus, a person may have a genetic makeup that predisposes them to Schizophrenia, but
exposure to environmental factors may be required for Schizophrenia to develop.
Genetic Factors
Genetic linkage studies have identified more than 100 potential susceptibility genes, but it is clear
that no single gene is responsible.
There are significant associations between polymorphisms in individual genes and the likelihood of
an individual developing Schizophrenia but there appears to be no single gene that has an
overriding influence.

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Some of the genes implicated in Schizophrenia are also associated with bipolar disorder.

In first degree relatives, the risk

of developing Schizophrenia is about 10%. But even in monozygotic (identical twins), one of whom
has Schizophrenia, the probability of the other being affected is only about 50%, pointing towards the
Environmental Factors
1. Possible predisposing factors: maternal virus infections, subtle Brain damage at birth or any
problems that may have stopped the baby’s Brain from getting enough oxygen.
2. Schizophrenia is also associated with a neurodevelopmental disorder affecting mainly the
cerebral cortex and occurring in the first few months of prenatal development. This view is
supported by Brain-imaging studies showing cortical atrophy apparent in the early course of the
disease which may increase with time and correlate with the progression of the disorder.
3. Childhood abuse.
4. Stressful events such as car accident, bereavement, moving home, social isolation and alientation.
5. Other environmental factors such as Cannabis/Crack/Amphetamines/LSD/Ecstasy
consumption in adolescence and early adulthood may reveal Schizophrenia/double the risk of
developing it.
NEUROANATOMICAL AND NEUROCHEMICAL BASIS OF SCHIZOPHRENIA

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Different symptoms of Schizophrenia appear to result from malfunctions in different neuronal

circuits.
Positive symptoms result from OVERACTIVITY of the mesolimbic Dopaminergic pathway
activating D2 receptors.
Negative symptoms result from the DECREASED ACTIVITY of the mesocortical Dopaminergic
pathway where D1 receptors predominate.
The main neurotransmitters involved in Schizophrenia are thought to be Dopamine and Glutamate.
Others include Serotonin and GABA (Gamma-AminoButyric Acid)
Dopamine – “There is Increased Dopamine in Schizophrenia in the Limbic Area of the Brain”
There are three major pathways involved with Dopamine and Schizophrenia:
1. Mesolimbic Pathway (sensory stimuli and movement): Overactive. Action on GABA
interneurons. Increased Dopamine activity.
2. Mesocortical Pathway (cognitive, reward and emotional behaviour): Underactive. Decreased
Dopamine release in cortex.
3. Tubero-Infundibular System (neuronal control of the Hypothalamic-Pituitary Endocrine
System): Underactive.
The original Dopamine theory of Schizophrenia was based on the indirect pharmacological
EVIDENCE in humans and experimental animals:
1.

Brain imaging studies have revealed an increased Dopamine synthesis and release in the striatum of
Schizophrenic patients.
2. Amphetamine (stimulant drug) releases Dopamine in the Brain and can produce in humans a
behavioural syndrome reminiscent of an acute Schizophrenic episode.
3. Potent D2-Receptor Agonists, such as Apomorphine/Bromocriptine, produce similar effects in
animals, and these drugs also exacerbate the symptoms of Schizophrenia patients.
4. Furthermore, Dopamine Antagonists (Chlorpromazine/Haloperidol) and drugs that block
neuronal Dopamine storage (eg, Reserpine) are effective in controlling the positive symptoms
of Schizophrenia and in preventing Amphetamine-induced behavioural changes. Clinical
efficacy of antipsychotic drugs is consistently achieved when D2-Receptor occupancy reaches
about 80%.
5. Dopamine supersensitivity occurs in Schizophrenia (D2high affinity states are increased).
6. Hallucinations are a side effect of Levodopa and Dopamine agonists used for Parkinson’s
Disease.

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7. In animals, Dopamine release causes a specific pattern of stereotyped behaviour that resembles
the repetitive behaviours sometimes seen in Schizophrenic patients.
Other Dopaminergic pathways in the Brain (Nigrostriatal) appear to function NORMALLY in
Schizophrenia.
*There are, however, exceptions to this theory:
- Up to one-third of patients fail to respond even when D2-Receptor blockade exceeds 90%
and Clozapine can be effective at much lower levels of block.
- An increase in Dopamine receptor density in Schizophrenia has been reported in some studies, but
not consistently, and the interpretation is complicated by the fact that chronic antipsychotic
drug treatment is known to increase Dopamine receptor expression.
Glutamate – “There is Decreased Glutamate in Schizophrenia”
In humans, Glutamate N-methyl-D-aspartate receptor (NMDA) antagonists such as
Phencyclidine, Ketamine and Dizocilpine can produce positive, negative and cognitive deficit
symptoms – in contrast to Amphetamine, which produces only positive symptoms.
It has therefore been postulated that Schizophrenia may result from disruption of Glutaminergic
neurotransmission (the NMDA Hypofunction Hypothesis).
1. In the Brains from Schizophrenic patients expression of the Glutamate Uptake Transporter
(VGLUT1) is REDUCED, which indicates a disruption of Glutaminergic nerve terminals.
2. There is a reduction in the function of NMDA Receptors.
3. Transgenic mice in which NMDA receptor expression is reduced (not abolished, because this is
fatal) show stereotypic behaviours and reduced social interaction that are features of human
Schizophrenia.
NEURODEGENERATION
The following factors are all suggestive of ongoing neurodegeneration in the disease:
1. Structural abnormalities in the Brains.
2. Absence of symptoms in early childhood.
3. The likelihood of positive symptoms becoming apparent before negative symptoms.
4. Reduced responsive to drugs with time.
5. Development of Dementia.
6. Progression of the disease.
The causes of such neurodegeneration are unclear at present but may involve Glutamate-induced
excitotoxicity.
ANIMAL MODELS
- There is a need for the development of animal models of Schizophrenia that simulate the positive,
negative and cognitive deficit components of this disorder.
- Models of cognitive deficits and negative symptoms are lacking.
- The development of such models is a major challenge that requires a better understanding of the
pathophysiological processes that underlie different symptoms.
- Schizophrenia presents as a heterogeneous disorder with sufferers exhibiting different
combinations of symptoms that may result from different neuronal abnormalities.
- Traditional models by and large reflect behaviours resulting from heightened Dopaminergic
transmission in the Brain.

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- Thus, they were likely to show positive results with drugs that have Dopamine receptor antagonist
activity.
- Models based on inhibition of NMDA function by Phencyclidine (PCP) and related drugs have
become popular in recent years.
- PCP causes a Schizophrenia-like syndrome. Schizophrenics are more sensitive to PCP.
- Various genetic models are also being examined.
- These have focused on proteins such as DISC-1 that are implicated in Schizophrenia and on
receptors and transporters for neurotransmitters such as Glutamate and Dopamine.
- However, as described above, the genetic basis of Schizophrenia is multifactorial and
environmental factors are also important.
- Thus, mutation of a single gene may provide only limited information.
DIAGNOSIS

 [UK] International Classification of Diseases: ICD-10

 [US] Diagnostic and Statistical Manual of Mental Disorders: DSM+5
Look in “Schizophrenia, Fast Facts” by Shon W Lewis and Robert W Buchanan (p 15 and 16).
TREATMENT

Treatment is currently based on the Dopamine Hypothesis of Schizophrenia, so pharmacologically,

most of the antipsychotics are Dopamine receptor
antagonists. However, many of them also act on
other targets, particularly 5-Hydroxytryptamine
(5-HT) Receptors, which many contribute to their
clinical efficacy.
The aim of treatment is:
- To improve psychotic symptoms.
- Reduce risk to patient.
- Reduce risk to others.
- Prevent relapse and readmission.
- Maximise benefits and minimise side effects.

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Efficacy of Antipsychotics
- Initial response: 1-2 weeks (most in 1st week).
- Full effect of dose change: 1-2 weeks.
- Full effect of antipsychotic: 4-6 weeks.
- 70% of patients will get better with 1st antipsychotic tried (atypical or typical).
- Less than 20% get better with second drug tried.
- 30% of patients are treatment resistant.
More than 40 different antipsychotic drugs are available for clinical use. These have been divided into
2 different groups:
1. First Generation/Typical/Conventional Anti-Psychotic Drugs.
2. Second-Generation/Atypical Anti-Psychotic Drugs.
The distinction between the first and second generation drugs are not clearly defined but rests on:
- Receptor profile.
- Incidence of Extra-Pyramidal Side Effects (EPSEs) – which are less in the second group.
- Efficacy (especially Clozapine) in “treatment resistant” group of patients.
- Efficacy against negative symptoms.
First Generation/Typical/Conventional Anti-Psychotics
These agents block many different mediators, including Histamine, Catecholamines, Acetylcholine
and 5-HT.
Antipsychotic potency generally runs parallel to activity on D2 receptors, but activities at other
receptors (α1, H1 and mACh receptors) may determine the unwanted side effect profile.
Linked to EPSEs and Prolactin.
Block D2 Receptors in the Striatum = EPSEs
Block D2 Receptors in the Hypothalamus = Prolactin

Drug Therapeutic Receptor NOTES

Class Affinity for
D1 / D2/ α1 /
H1 / mACh/
5-HT2A
Chlorpromazin Phenothiazine Affinity for - Extrapyramidal Side Effects.
e Class all - Sedating.
(Low Potency) - Hypotension.
Fluphenazine, - Increased prolactin.
Trifluperazine - Hypothermia.
are similar but - Antiadrenergic/antihistamine/
do not cause anticholinergic side effects.
Jaundice, cause - Hypersensitivity reactions.
less hypotension - Obstructive Jaundice.
but more EPSEs - Cognitive impairment.
Haloperidol Butyrophenone NOT mACh - Strong Extrapyramidal Side Effects.
(High Potency) Class - Non-sedating.
- Hypotension.
- Increased prolactin.
- Hypothermia.
- Fewer anticholinergic side effects.

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- Hypersensitivity reactions.
- No Jaundice.
- Available as depot preparation
(storage in large quantity).
- Cognitive impairment.
Flupentixol Thioxanthine NOT α1 or - Extrapyramidal Side Effects.
(High Potency) Class mACh - Sedating.
- Hypotension.
Clopentixol is - Increased prolactin.
similar - Restlessness.
- Available as depot preparation.
- Cognitive impairment.
Sulpiride Benzamides NONE - Extrapyramidal Side Effects.
EXCEPT D2 - Non-sedating.
Amisulpride and - NO Hypotension.
Pimozide are - Increased prolactin.
similar - Selective D2/D3 Antagonist.
- Increases alertness in apathetic patients
(patients showing or feeling no
interest/enthusiasm).
- Poorly absorbed.

Second-Generation/Atypical Anti-Psychotics
Second generation drugs are more expensive. There must be a balance between the costs regarding
hospitalisation, social services, family problems and the effect of the drug.
Linked to weight gain, Diabetes, Dyslipidaemia and Metabolic Syndrome.

Drug Therapeutic Receptor Notes

Class Affinity for
D1 / D2/ α1 /
H1 / mACh/ 5-
HT2A
Risperidone NOT mACh - Extrapyramidal Side Effects
(significant risk at high doses).
Usually first - Sedating.
line treatment - Hypotension.
for newly - Weight gain.
diagnosed - Possibly effective against negative
patients. symptoms.
- Potent on D4 Receptors.
- Paliperidone is a metabolite.
- Available as depot preparation.
Quetiapine Affinity for all - NO/LOW INCIDENCE OF
Extrapyramidal Side Effects.
- Sedating.
- Hypotension.
- Tachycardia.
- Drowsiness.
- Dry mouth.
- Constipation.
- Weight gain.
- No increase in prolactin secretion.

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- 5-HT1A Partial Agonist.

- Short-acting (plasma half-life ~6h).
Aripiprazole NOT mACh - NO Extrapyramidal Side Effects.
- Little sedation.
- No hypotension.
- Long-acting (plasma half-life ~3
days).
- 5HT1A Partial Agonist.
- No effect on prolactin secretion.
- No weight gain.
- Available as depot preparation.
Ziprasidone NOT mACh - Extrapyramidal Side Effects.
- Non-sedating.
- Hypotension.
- Tiredness.
- Nausea.
- No weight gain.
- Possibly effective against negative
symptoms.
- Short-acting (~8h).
- Available as depot preparation.
Clozapine Benzodiazepine Affinity for all - High antipsychotic activity but
LIKELY TO s Class relatively low affinity for the D2
BE IN Receptor.
EXAM!!!!! - NO Extrapyramidal Side Effects.
- Sedating.
Olanzapine is - Hypotension.
less sedative, - Hypersalivation.
without risk of - Anticholinergic side effects.
agranulocytosis - Weight gain.
, but there is - No effect on prolactin.
questionable - Shows efficacy in “treatment
efficacy in resistant patients” and reduces
treatment- incidence of suicide.
resistant - Effective against negative and
patients. positive symptoms.
- Agranulocytosis (deficiency of
Olanzapine granulocytes).
also usually - Reversible, potentially fatal loss of
first line neutrophils, basophils and
treatment for eosinophils only seen with
newly clozapine.
diagnosed - Regular blood tests weekly for 18
patients. weeks and then every 2 weeks for
the rest of Year 1. Then monthly.
- RULE: NO BLOOD = NO
CLOZAPINE.
- Constipation (may be fatal).
Remoxipride Benzamides
Others: Sertindole, Zotepine, Paliperidone, Lurasidone

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Atypicals are thought to be more effective on negative symptoms and have fewer EPSEs possibly
because:

- High 5HT2A/D2 binding affinity

ratio.
- Low D2 Receptor affinity.
- Fast dissociation from D2
Receptors.

Abrupt cessation of antipsychotic drug

administration may lead to a rapid onset psychotic episode.
The clinical efficacy of antipsychotic drugs in enabling Schizophrenic patients to lead more normal
lives has been demonstrated in many controlled trials.
However, antipsychotic drugs have significant drawbacks:
1. Not all patients respond to drug therapy. It is recommended to try Clozapine in patients who
are resistant to other antipsychotic drugs. The 30% of patients who do not respond are classed as
“treatment-resistant” patients. The reason for the difference between response and unresponsive
patients is unknown as present, although there is some evidence (not conclusive) that
polymorphisms within the family of Dopamine and 5-HT receptors may be involved.
2. While they control the positive symptoms effectively, most are ineffective in relieving the
negative symptoms and cognitive impairment.
3. They induce a range of side effects that include extrapyramidal motor, endocrine and sedative
effects that can be severe and limit patient compliance.
4. They may shorten survival through cardiac (pro-arrhythmic) effects.
Second-generation antipsychotic drugs were believed to overcome these shortcomings to some
degree. However, only some of the second-generation anti-psychotic drugs examined showed better
overall efficacy. There is a definite need for the development of new treatments.
UNWANTED EFFECTS
EXTRAPYRAMIDAL MOTOR DISTURBANCES
- Antipsychotic drugs produce two main kinds of motor disturbance in humans: acute dystonias
and tardive dyskinesias, collectively termed EXTRAPYRAMIDAL SIDE EFFECTS.
- These all result directly or indirectly from D2 receptor blockade in the nigrostriatal pathway.
- Extrapyramidal side effects constitute one of the main disadvantages of first-generation anti-
psychotic drugs.
- Second-generation drugs were thought to have less tendency to produce EPSEs, but a long-term
study concluded that they too can induce EPSEs.
Acute Dystonias
1. Acute Dystonias are involuntary movements and tightening/twisting of a limb (restlessness,
muscle spasms, protruding tongue, fixed upward gaze, neck muscle spasm), often accompanied by
symptoms of Parkinson’s Disease.
2. It can be painful.

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3. Occurs commonly in the first few weeks, often declining with time, and are reversible on
stopping drug treatment.
4. The timing is consistent with block of the Dopaminergic Nigrostriatal pathway.
5. Treatment: anticholinergics such as Procyclidine. Reduce dose.
Tardive Dyskinesia
1. They syndrome consists of involuntary, repetitive, purposeless movements, often of the face
and tongue, but also of the trunk and limbs, which can be severely disabling.
2. Features may include grimacing, tongue protrusion, lip smacking, puckering and pursing,
rapid eye blinking and rapid movements of the arms and legs.
3. Develops after months or years in 20-40% of patients treated with first-generation
antipsychotic drugs and is one of the main problems of antipsychotic therapy.
4. It is disabling and often irreversible, which often gets worse when anti-psychotic therapy is
stopped and is resistant to treatment.
5. It can be prevented by reducing/stopping treatment sometimes but this is not usually an option.
6. It resembles that seen after prolonged treatment of Parkinson’s Disease with Levodopa.
7. The incidence depends greatly on drug, dose and age (being commonest in patients over 50).
8. Treatment: Stop anticholinergic. Change to atypical. Reduce dose.
Akathisia
1. Feeling of inner restlessness.
2. Unable to sit or keep still.
3. Compelling need to be in constant motion.
4. Rocking while standing or sitting.
5. Lifting the feet as if marching on the spot.
6. Crossing and uncrossing the legs while sitting.
7. Has been linked to violence and suicide if left untreated.
8. Treatment: Propanolol (anticholinergics generally unhelpful). Reduce dose.
Akinesia
1. Absence/loss/impairment of the power of voluntary movement.
Pseudoparkinsonism – tremor, rigidity, salivation, expressionless face. Treatment: reduce dose and
use atypical. Give anticholinergic – Procyclidine.
ENDOCRINE EFFECTS
Blocking D2 Receptors can increase plasma prolactin concentration.
What is Prolactin?

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Prolactin is a hormone synthesised and stored in the anterior pituitary gland. It stimulates milk
production and progesterone production in the ovary. Prolactin is under the inhibitory control of
Dopamine.
Hyperprolactinaemia can result in:
- Sexual dysfunction (erectile/orgasmic/libido)
- Amenorrhoea (periods stop).
- Galacotorrhea (breast swelling, pain and lactation which can occur in men as well as women).
- Anovulation (failure to release ova over time exceeding three months).
- Gynaecomastia (enlargement of man’s breast).
- Reduced bone mineral density (Osteoporosis – must be monitored in teens).
- Increased risk of breast cancer.
OTHER UNWANTED EFFECTS
Most antipsychotic drugs block a variety of receptors, particularly noradrenaline (α), histamine
(H1), acetylcholine (muscarinic) and 5-HT receptors.
This gives rise to a wide range of side effects.
They can produce sexual dysfunction – decreased libido and decreased arousal as well as erection
and ejaculation difficulties in men – through block of dopaminergic, adrenergic and muscarinic
receptors (eg, Risperidone, Clozapine).
Drowsiness and sedation tends to decrease with continued use.
Antihistamine (H1) activity is a property of some phenothiazine antipsychotics (eg, Chlorpromazine
Quetiapine, Olanzapine, Clozapine and Methotrimeprazine) and contributes to their sedative and
antiemetic properties, but not to their antipsychotic action.
Antimuscarinic effects: dry mouth, blurred vision, constipation, urinary retention (eg,
Chlorpromazine, Clozapine)
Jaundice (yellowing of the skin) – occurs with older phenothazines such as chlorpromazine. Usually
mild.
Urticarial skin reactions are common but usually mild.
Antipsychotic Malignant Syndrome, Leukopenia and Agranulocytosis can happen but is rare.

Weight gain is a common and

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Increased risk of Diabetes occurs with several second-generation antipsychotic drugs.

Increased risk of Cardiovascular Disease

also occurs with several second-generation
antipsychotic drugs. Antipsychotic drugs can
prolong the QT interval in the heart, giving rise to
arrhythmia and risk of sudden death.

Metabolic Syndrome

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Dyslipidaemia

Neuroleptic Malignant Syndrome

PRESCRIBING IN SCHIZOPHRENIA

For patients newly

diagnosed with Schizophrenia, offer oral antipsychotic mediation (typical or atypical).
The relationship between the plasma concentration and the clinical effect of antipsychotic drugs is
highly variable, and the dosage has to be adjusted on a trial-and-error basis.
This is made even more difficult by the fact that at least 40% of patients fail to take drugs as
prescribed.
Joint decisions should be made by both doctor and patient.
Provide information and discuss benefits and side effects of each drug.
Offer ECGs for all in patients, at risk or past history of cardiovascular disease, in Statistical Process
Control.
Antipyschotics should not be regularly co-prescribed.

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The plasma half-life of most antipsychotic drugs is 15-30h, clearance depending entirely on hepatic
transformation by a combination of oxidative and conjugative reactions. Most antipsychotic drugs
can be given orally or in urgent situations by intramuscular injection. The drug acts for 2-4 weeks.
Consider depot if preferred by patient or if non-concordant (non-consistent).
Slow release (depot) preparations are available, in which the active drug is esterified with heptanoid
or decanoic acid and dissolved in oil.
If no response to Clozapine when used as a last resort, augment with a second antipsychotic.
CBT (Cognitive Behavioural Therapy) is an option but only 1 in 8 people can access it.
Conclusion
- Balance efficacy and tolerability.
- Maximise benefit and minimise side effects.
- Every time a patient relapses they have a lesser chance of recovery…patient choice is also
key.
- Must keep in contact with GP  keep communication up.
- “All patients should have access to specialist Pharmacist within easy reach”.
- If plans to change treatment, don’t wait too long  it’s not going to get better if left untreated.
FUTURE DEVELOPMENTS
- The cognition enhancer Modafinil may be useful in treating the cognitive deficit in
Schizophrenia.
- Preclinical and clinical studies have provided encouraging evidence that orthosteric and
allosteric agonists of Metabotropic Glutamate Receptors mGluR 2 and mGluR3 are effective
in treatment of the positive symptoms of Schizophrenia.
Also in various stages of development are:
- NMDA Receptor Positive Allosteric Modulators
- AMPA/Kainate Agonists/AMPAkines/AMPAmodulators
- α2 Agonists/Antagonists
- α7 nicotinic receptor agonists
- α4/β2 Nicotinic Agonists
- histamine H3 antagonists
- 5-HT 6 antagonists
- COMT inhibitors
- Inhibitors of phosphodiesterase (PDE10)
Selective agonist action at M1 Muscarinic Receptors (either orthosteric or allosteric) has
significant potential for cognition enhancement in both Schizophrenia and Alzheimer’s Disease but
to date drug development has been hampered by a lack of selectivity across muscarinic receptor
subtypes.
QUESTIONS

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MCQ: Concerning antipsychotic drugs:

A. The antipsychotic potency of drugs increases in proportion to their binding affinity for Dopamine
receptors of the D1 subtype. NO - Antipsychotic potency generally runs parallel to activity on
D2 receptors.
B. Extrapyramidal Side Effects of antipsychotic drugs are used by their blocking activity at
muscarinic-type acetylcholine receptors in the corpus striatum. NO - Block D2 Receptors in the
Striatum = EPSEs
C. They reduce prolactin secretion by blocking Dopamine receptors in the hypothalamus. NO –
Prolactin secretion is INCREASED by blocking Dopamine receptors.
D. They are more effective in controlling positive rather than negative symptoms of schizophrenia:
While they control the positive symptoms effectively, most are ineffective in relieving the
negative symptoms and cognitive impairment.
MCQ: The most likely cause of Schizophrenia is currently thought to be:
A. A deficiency of Dopamine in the limbic system.
B. An excess of Dopamine in the limbic system.
C. An excess of Serotonin (5-HT) in the limbic system.
D. A deficiency of Serotonin (5-HT) in the limbic system.
Section B Question 1 mark out of 5 marks: Explain briefly what might be the basis of following
decisions in the drug treatment of mental illness: A typical neuroleptic, rather than neuroleptic in a
patient with resistant Type 2 Schizophrenia.
Type 2 Schizophrenia indicates that the patient has negative symptoms. Atypicals are thought to be
more effective at treating negative symptoms (and there are less extrapyramidal side effects). As the
patient is treatment resistant, Clozapine would have to be chosen as the “last resort” choice of
treatment. Clozapine is atypical. (And if the patient still did not respond, then a second antipsychotic
would have to augmented).
Section B 2 marks out of 5 marks: Which ONE of the methods listed in the options below is the
MOST IMPORTANT for monitoring therapy with each of the following drugs?

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Haloperidol C
Clozapine B
Options – A method may be used once, more than once or not at all. Enter the letter corresponding to
the correct answer in the box alongside the drug in the table above:
A. Therapeutic monitoring of serum level.
B. Full blood count.
C. Control of symptoms of disease being treated.
D. Measure renal function.
E. Presence of adverse effects.
Section B (2marks/5marks): Explain briefly what might be the basis of the following decisions in
the drug treatment of illness of the nervous system:
An atypical neuroleptic chosen for first episode Schizophrenia:
1. The guidance from NICE recommends that oral atypical antipsychotic agents should be
considered in the choice of first-line treatment options for patients with newly diagnosed
Schizophrenia because such patients are known to be “more susceptible to the adverse effects of
treatment, which may subsequently impact on their adherence to future therapy and on their
longer-term prognosis”.
2. The central tenet of the guidance is the importance of avoiding antipsychotic-induced
movement disorders.
3. Low doses of atypicals seem unlikely to cause EPSEs. Some atypicals are less likely to cause
EPSEs than typicals.
4. Atypical antipsychotic drug provide superior efficacy, reduced side effects, and due to the
prospect of better compliance, their greatest impact may be when used in patients at the beginning
of their illness. 
Section C 20 Marks: Read the patient details that follow and answer the questions in the spaces
provided. Answers in note form are acceptable.
Ms. PS Student
Ms PS has had to drop out of her second year University Biology course. She started missing classes
and getting very poor marks, and eventually had what friends called a “nervous breakdown” just
before exams. She was admitted involuntarily to a psychiatric hospital under a section of the Mental
Health Act after becoming increasingly disturbed. She claimed initially that other students were
plotting against her to prevent her from attending, then said the University authorities were planning
to fail her. Later she complained the United Nations had decided to imprison her because she had
discovered that Biology was the meaning of the Universe. She claimed to hear them discussing her
case via a mobile phone implanted in her skull. Her mother described her as a solitary child,
especially since the time she had separated from her alcoholic father when 13 years old.
What do you think is wrong with PS?
I think that PS is Schizophrenic.
Which clinical features brought you to this conclusion?
Given that she thinks other students are “plotting against her to prevent her from attending”
(delusional – paranoid in nature), the “University authorities were planning to fail her” (delusional –
paranoid in nature) and that the United Nations had been discussing her via a “mobile phone
implanted in her skull” (hallucinations in the form of voices) and decided to “imprison her because

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she had discovered Biology was the meaning of the Universe”, the clinical symptoms indicated are a
combination of thought disorder, hallucinations and delusions.
What other symptoms might PS display if the disease progresses?
If her symptoms stay positive, then:
Positive (Type 1)
7. Catatonia (immobility or purposeless motor activity).
8. Abnormal, disorganised behaviour (stereotyped movements – physical movements that are
aimless and repetitive, disorientation and occasionally aggressive behaviour).
9. Thought disorder (comprising wild trains of thought, delusions of grandeur, garbled sentences
and irrational conclusions) and Thought Broadcasting (others can hear my thoughts).
10. Hallucinations (often in the form of voices - which may be exhortatory in their message - but
also smelling/seeing/feeling).
11. Delusions (often paranoid in nature).
12. Feeling of being controlled (thoughts vanishing/thoughts not your own/body is being taken over
and controlled by someone else).
If there are a mix of positive and negative symptoms, then:
Negative (Type 2)
7. Flattening of emotional responses.
8. Anhedonia (inability to experience pleasure).
9. Reluctance to perform everyday tasks.
10. Social withdrawal.
11. Self-Neglect (not washing/tidying).
12. Affective Blunting (not interested in friends or family).
Neurocognitive Impairment
3. Deficits in cognitive function (eg, attention, memory).
4. Executive function (eg, doing tasks, planning).
In addition:
5. Self-punishment.
6. Anxiety.
7. Depression.
8. Guilt.
The symptoms become more prominent with age and time (progressive, not stationary).
This leads to suicide attempts in up to 50% of cases, about 10% of which are successful.
A characteristic feature of Schizophrenia is “SELECTIVE ATTENTION”. Whereas a normal
individual quickly accommodates to stimuli of a familiar or inconsequential nature, and responds only
to stimuli that are unexpected or significant, the ability of Schizophrenic patients to discriminate
between significant and insignificant stimuli seems to be impaired.
For example, the ticking of a clock may command as much attention as the words of a companion. Or
a chance thought, which a normal person would dismiss as inconsequential, may become an
irresistible imperative (essential or urgent thing).
What is the relevance of her social history?

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The relevance of her social history is that (assuming the event of being separated from her father was
traumatic), it could be the environmental factor which caused the Schizophrenia. Or it could be the
predisposing factor of her developing Schizophrenia (if she had a genetic makeup that predisposed her
to Schizophrenia, then the environmental factor would have caused the disease to develop).
What advice might the GP provide?
The GP might have advised that PS begin antipsychotics, that she be in regular contact with the GP
and that a specialised Pharmacist be in easy reach.
The GP might also direct her to Cognitive Behavioural Therapy (although this would be difficult as
only 1 in 8 people can access it).
What is the management likely to be on admission?
Verbally engaging an agitated patient should always be tried in the setting of an appropriately safe
emergency room environment with available security personnel. Oral medications should be offered
and, if accepted, can be as effective as IM medications.
On admission, as the patient was “admitted involuntarily to a psychiatric hospital under a section of
the Mental Health Act after becoming increasingly disturbed”, this indicates that she might not be
compliant, in which case a antipsychotic should be given with a fast onset of action. So, upon
choosing, the drug would be given by an intramuscular injection.
The management (after looking at her past medical history and seeing which is appropriate) would be
to choose from the Typical Antipsychotics and Atypical Antipsychotics after discussing with the
patient and the carer which is preferred (if this discussion is possible).
What will be the subsequent management, and what adverse effects will PS be warned about?
If a typical antipsychotic was chosen, then PS would be warned particularly about:
Extrapyramidal Side Effects and the increase of Prolactin production.
EPSEs: (acute dystonias, tardive dyskinesia, akathisia, akinesia).
Prolactin: galactorrhea.
If an atypical antipsychotic was chosen, then PS would be warned particularly about: weight gain,
Diabetes, Dyslipidaemia and Metabolic Syndrome.
The side effects for typicals and atypicals would vary however, depending on the exact choices. For
instance, some are sedating, some aren’t, some cause hypotension, some don’t etc.
The other side effects she would be warned about are:
F. They can produce sexual dysfunction – decreased libido and decreased arousal as well as
erection and ejaculation difficulties in men – through block of dopaminergic, adrenergic and
muscarinic receptors (eg, Risperidone, Clozapine).
G. Drowsiness and sedation tends to decrease with continued use.
H. Antihistamine (H1) activity is a property of some phenothiazine antipsychotics (eg,
Chlorpromazine Quetiapine, Olanzapine, Clozapine and Methotrimeprazine) and contributes to
their sedative and antiemetic properties, but not to their antipsychotic action.
I. Antimuscarinic effects: dry mouth, blurred vision, constipation, urinary retention (eg,
Chlorpromazine, Clozapine)
J. Pseudoparkinsonism – tremor, rigidity, salivation, expressionless face. Treatment: reduce dose
and use atypical.

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K. Jaundice (yellowing of the skin) – occurs with older phenothazines such as chlorpromazine.
Usually mild.
L. Urticarial skin reactions are common but usually mild.
M. Antipsychotic Malignant Syndrome, Leukopenia and Agranulocytosis can happen but is rare.
N. Weight gain is a common and troublesome side effect.
O. Increased risk of Diabetes occurs with several second-generation antipsychotic drugs.
P. Increased risk of Cardiovascular Disease also occurs with several second-generation
antipsychotic drugs. Antipsychotic drugs can prolong the QT interval in the heart, giving rise to
arrhythmia and risk of sudden death.
Q. Metabolic Syndrome
R. Dyslipidaemia
S. Neuroleptic Malignant Syndrome
She should go for regular ECGs if she has a past medical history of Cardiovascular Disease.
From there onwards, if the patient did not respond to the first antipsychotic, another one would be
chosen and if that did not work, than Clozapine would be the last resort. If she ended up on Clozapine,
then she would need regular blood tests weekly for 18 weeks and then every 2 weeks for the rest
of Year 1. Then monthly.
If Clozapine as a last resort failed, then Clozapine would have to be given in conjunction with another
antipsychotic.
If PS got better, then she over time she could choose whether a slow release depot preparation would
be suited for her.
Section C 20 Marks: Read the patient details that follow and answer the questions in the spaces
provided. Answers in note form are acceptable.
David S, 25 years old, obese and unemployed, was admitted compulsorily to an acute psychiatric unit
4 months ago. He had been found wandering by himself at night, claiming he was being followed by
“spies who controlled him with rays”.
At the age of 17, while he seemed to be doing well in his A-Levels he has a “nervous breakdown”. He
dropped out of school and left home, becoming involved in drugs and petty crime.
At age 19, he was arrested for shoplifting. The police found him incoherent and suspicious, accusing
them of being agents for an alien power sent to destroy him; so they referred him to a psychiatrist.
He was prescribed Haloperidol, eventually being stabilised on a dose of 4mg daily. He subsequently
complained of stiffness and shaking, so Procyclidine 5mg twice daily was added. He has been in a
psychiatric hospital several times since then; usually this follows a time when he fails to take his
medication.
In hospital this time he was given a single intramuscular dose of 10mg Olanzepine. Following this he
was switched to Olanzapine 10mg daily by mouth. He was discharged after 3 months on the same
medication.
What do you think accounted for David’s initial symptoms at age 17? (2 marks)

Which initial features or symptoms brought you to this conclusion? (2 marks)

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Comment on the symptoms reported by the police at age 19 (2 marks)

David was accusing the police of being “agents for an alien power sent to destroy him”. This suggests
that David is delusional (paranoid in nature) and possibly hallucinational (visually).
Comment on his drug therapy after referral by the police to a psychiatrist (3 marks)
David has been given a typical antipsychotic, and the Procyclidine to deal with the pseudo-
Parkinsonism (extrapyramidal side effects) which are a result of the typical antipsychotic. If this is not
working for him (he does not seem to be compliant as he has been admitted several times since then),
he should possibly change for an atypical with less extrapyramidal side effects such as
OLANZAPINE.
Comment on the several subsequent admissions (2 marks)
Quite clearly, he is not that compliant with his medication. He should be asked why he is not taking
his medication as he should and what the problems are. It might be better to change the drug. Perhaps
a Pharmacist should have a Medicines Use Review.
What does “compulsory admission” mean and why was it done? (2 marks)
Compulsory Admission is:
A mandated admission of a patient in the UK to hospital after a formal mental health assessment unde
r the UK’s Mental Health Act 1983, 2007, which is carried out by an Approved Mental
Health Worker (formerly by an Approved Social Worker) in conjunction with a Section 12(2)-
approved doctor and a consultant psychiatrist. 
Under the Act, the person must have a mental disorder or disability of mind (alcohol or drugaddictio
n alone are insufficient to detain a person under the Act), require hospital detention for assessment 
or treatment, and the detention must be necessary in the interests of the patient's health or safety, or wi
th a view to the protection of others.
Under the Mental Health Act, if you have a “mental disorder”, you can be admitted to hospital against
your wishes (becoming a formal patient) provided the processes in the Act are followed. Part 2 of the
Act is a group of sections that covers your rights if this happens to you.
In this case, David was admitted as he was doing things he should not (shoplifting), and could have
become a danger to the police, believing they were “an alien power sent to destroy him”.
Comment on his management in his most recent admission (2 marks)
Due to the extrapyramidal side effects and lack of compliance, it seems that David was switched to an
atypical, which does not have extrapyramidal side effects. He was probably not discharged until the
healthcare professionals were sure that he was stable on Olanzapine and would be willing to take it
from there onwards.
What are the management options once discharged, especially if he remains non-compliant? (3
marks)
Other management options include slow release (depot) preparations, in which the active drug is
esterified with heptanoid or decanoic acid and dissolved in oil. Slow release means that he will not
have to take the medication daily (eg, every two weeks instead of daily).
He could also be offered Cognitive Behavioural Therapy (if he can get access to it), and advised to see
specialist Pharmacist. There should also be a healthcare professional (such as a GP) within reach.

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What is David’s prognosis? (2 marks) Prognosis – likely outcome of the situation.

If David is compliant with his medicine, there should be no reason why he cannot lead a normal life
there onwards.
However, if he is non-compliant and his symptoms worsen, he could be kept in a Mental Hospital or it
could lead him to committing suicide.
Section B 5 Marks: Explain how the Risperdal Consta formulation sustains the release of
Risperidone for a period of approximately two weeks
Section B 5 Marks: Using a specific example from the formulations currently listed in the British
National Formulary, briefly explain the mechanism for sustained release of an antipsychotic drug that
is formulated using polymers
Risperdal Consta is a powder formulation.
The polymer itself has to be degraded first. They are biodegradable so they degrade first to allow the
portioning of Risperidone into the plasma for absorption.

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