DRUGS USED TO TREAT

SCHIZOPHRENIA

L.K. Montane Jaime

MDSC 3313 2011

Objectives
1. Recognize, in clinical case study problems the main diagnostic criteria of
schizophrenia
2. Describe the dopamine theory of schizophrenia, data supporting and refuting.
 3. Describe dopamine, how it is synthesized and the various dopaminergic pathways.
4. Describe the serotonin theory of schizophrenia, data supporting and refuting.
5. Describe serotonin, how it is synthesized and the various serotonergic pathways.
6. Recognize differences between typical and atypical antipsychotics in clinical case
study problems particularly with regard to strength of binding to dopamine and
serotonin receptors and adverse effects.
7. When choosing an antipsychotic drug what are the implications of these being
high or low potency antipsychotics.
8. Recognize signs and symptoms of extrapyramidal side effects (acute and chronic)
and explain how antipsychotic drugs may lead to their appearance.
9. Explain the pharmacological basis for the treatment of antipsychotic-induced
acute and chronic extrapyramidal side effects.
10. When prophylactic treatment for extrapyramidal side effects should be considered
and what are the medications available?
11. Describe the neuroleptic malignant syndrome and how it should be managed.
12. Recognize other relevant typical antipsychotic side effects in clinical case study
problems including seizures, galactorrhea and oligomenorrhea, weight gain, and
effects on sexual function and explain their occurrence based on their effects
mediated by different receptors types.
13. Choose atypical antipsychotics in clinical case study problems based on strength
of binding to dopamine, serotonin and autonomic receptors and their relation to
adverse effects.
14. Describe the effects of clozapine and olanzapine on glucose and triglyceride
levels.
15. State the routes of administration of antipsychotic drugs.

Schizophrenia

Schizophrenia is a major psychotic disorder. Its essential features consist of a mixture of

characteristic signs and symptoms that have been present for a significant length of time
during a 1-month period (or for a shorter time if successfully treated), with some signs of

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the disorder persisting for at least 6 months.
(http://www.psych.org/clin_res/pg_schizo_2.cfm)

Schizophrenia can be one of the most tragic of the various mental illnesses, and perhaps
one of the most tragic among the broad range of illnesses that affect human beings. The
original name for the disorder was "dementia praecox," which means a serious illness that
affects mental function and begins early in life. It was given this name when it was
identified at the turn of the century, in order to differentiate it from a related illness,
dementia in the elderly, which later came to be known as Alzheimer's disease. Both these
diseases were identified and differentiated from one another at about the same time in one
of the greatest departments of psychiatry of all time, that of Emil Kraepelin in Munich.
To the average person Kraepelin’s name is unfamiliar, while the name of his protégé,
Alzheimer, survives, because it is used to designate another important mental illness.
Schizophrenia would probably best be named Kraepelin’s disease, but instead we call it
schizophrenia, which was chosen a few years later by the Swiss psychiatrist, Bleuler, in
order to reflect the fact that the illness produces a fragmenting ("schizo") of the various
components of the mind ("phrenia").

Etiology

There have been dramatic advances in neuroimaging technology that permit scientists to
study brain structure and function in living individuals. Many studies of people with
schizophrenia have found abnormalities in brain structure (for example, enlargement of
the ventricles and decreased size of certain brain regions) or function (for example,
decreased metabolic activity in certain brain regions). However, these abnormalities are
quite subtle and are not characteristic of all people with schizophrenia, nor do they occur
only in individuals with this illness.

Microscopic studies of brain tissue after death have also shown small changes in
distribution or number of brain cells in people with schizophrenia. It appears that many
(but probably not all) of these changes are present before an individual becomes ill, and
schizophrenia may be, in part, a disorder in development of the brain.

Developmental neurobiologists funded by the National Institute of Mental Health

(NIMH) have found that schizophrenia may be a developmental disorder resulting when
neurons form inappropriate connections during fetal development. These errors may lie
dormant until puberty, when changes in the brain that occur normally during this critical
stage of maturation interact adversely with the faulty connections. This research has
spurred efforts to identify prenatal factors that may have some bearing on the apparent
developmental abnormality.
In other studies, investigators using brain-imaging techniques have found evidence of
early biochemical changes that may precede the onset of disease symptoms, prompting
examination of the neural circuits that are most likely to be involved in producing those
symptoms. Meanwhile, scientists working at the molecular level are exploring the genetic
basis for abnormalities in brain development and in the neurotransmitter systems
regulating brain function.

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Genetics

It has long been known that schizophrenia runs in families. People who have a close
relative with schizophrenia are more likely to develop the disorder than are people who
have no relatives with the illness (Figure 1). For example, a monozygotic (identical) twin
of a person with schizophrenia has the highest risk – 40 to 50 percent – of developing the
illness. A child whose parent has schizophrenia has about a 10 percent chance. By
comparison, the risk of schizophrenia in the general population is about 1 percent.

2.02. Concordance for Lifetime Risk

shared DNA
of Schizophrenia
100% identical twins
fraternal twins
children
50%
siblings
parents
half siblings
grandchildren
25%
nephews/nieces
uncles/aunts

12.5% 1st cousins

general population

0% 10% 20% 30% 40% 50%

Biology of Psychotic Behavior | Theories of SZ | Classification of Antipsychotics | Mechanism of Action | Adverse Effects | Clinical Efficacy
A.L. Padjen U8 Antipsycho 2002 12

Scientists are studying genetic factors in schizophrenia. It appears likely that multiple
genes are involved in creating a predisposition to develop the disorder The strongest
evidence to date leads to chromosomes 13 and 6 but remains unconfirmed. Researchers
have discovered evidence for the existence of a gene on Chromosome 1 (1q21-q22) that
appears to confer vulnerability to Schizophrenia. Most recently, in February 2010, a link
between schizophrenia and the vasoactive intestinal peptide receptor 2 (VIPR2) was
reported. This receptor is expressed in the nervous system, in blood vessels and the
gastrointestinal tract. When the expression of the VIPR2 gene in blood cells from the
patients with schizophrenia was measured, it was found that individuals with mutations
had greater expression of VIPR2 and greater activity of the receptor.

The Dopamine Theory of Schizophrenia

In 1952, Henri Laborit, a surgeon in Paris, was looking for a way to reduce surgical
shock in his patients. Much of the shock came from the anaesthesia, and if he could find a
way to use less, his patients could recover quicker. He knew that shock was the result of
certain brain chemicals and looked for a chemical that might counteract these. He tried
antihistamines. He was so struck by the effect on his patients, especially with a drug

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called chlorpromazine (Thorazine) he thought the drug must have some use in psychiatry.
A fellow surgeon passed the word to his brother-in-law, the psychiatrist Pierre Deniker.
Deniker's interest was piqued and he ordered some chlorpromazine to try on his most
agitated, uncontrollable patients. The results were stunning. Patients who had stood in
one spot without moving for weeks, patients who had to be restrained because of violent
behavior, could now make contact with others and be left without supervision
(http://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html.)

Following the assumption that an exogenous compound can only exert an effect by acting
at pre-existing receptors within the body, researchers looked for endogenous compounds
that shared similar chemical properties with chlorpromazine. What they found was
dopamine.

Dopamine
Dopamine is a natural neurotransmitter which
belongs to the catecholamine group that, in turn,
belongs to the wider group of neurotransmitters: the
monoamines. As you should remember a
monoamine is any molecule that contains a single
amine group (—NH2). As a catecholamine besides
containing the amine group it also has a “cathechol
nucleus” which is composed of a benzene ring with two adjacent hydroxyl groups (—
OH) (Figure 2).

Dopaminergic Neurons

Dopamine neurons synthesize dopamine from the amino acid tyrosine, which is
converted to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase.
Dihydroxyphenylalanine is converted to dopamine by the enzyme DOPA decarboxylase
(or aromatic amino acid decarboxylase) which is found in the cytoplasm. Dopamine can
be further metabolized to norepinephrine by the enzyme dopamine--hydroxylase, in
neurons containing the enzyme (Figure 3).

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Dopamine Pathways

There are four major dopamine pathways (Figure 4). They include:

1. The Mesolimbic Pathway

which originates in the Ventral
Tegmental Area (VTA) and projects
toward limbic structures, including
the Nucleus Accumbens and
Amygdala. Dopamine hyperactivity
in this limbic system projection is believed to
be associated with the positive symptoms of
schizophrenia.

2. The Mesocortical Pathway, which originates in the VTA of the midbrain and
projects into the prefrontal, temporal, and frontal cortices, plays an important role in
cognition, communication, and social activity. Diminished dopamine activity in the
frontal cortex is postulated to be associated with the negative symptoms of
schizophrenia.

3. The Nigroneostriatal Pathway which originates from cells in the substantia

nigra and projects to the striatum (Caudate, Putamen Nucleus which are components of
the Basal Ganglia). This circuit mediates extrapyramidal symptoms.

4. The Tuberoinfundibular Pathway projects from cells in the Arcuate Nucleus

to the Median Eminence; The released dopamine acts on the pituitary gland, where it
controls the release of prolactin.

Dopamine can be taken back up into neurons after release via the dopamine transporter,
or metabolized by monoamine oxidase (to 3,4,-dihydroxyphenylacetic acid) or catechol-
O-methyltransferase (to 3-methoxytyramine). These enzymes are major mechanisms for

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inactivation of catecholamines (and monoamines). Action by both enzymes results in the
formation of homovanillic acid (3-methoxy-4hydroxy-phenylacetic acid).

Dopamine Receptor Subtypes

There are five types of dopamine receptors. These are D1, D2, D3, D4, and D5. All of
these receptor subtypes work through the G-protein-linked receptor. Once activated
the D1 and D5 receptors activate adenylyl cyclase leading to the production of cyclic
adenosine monophosphate (cAMP). The D2, D3, and D4 receptors, on the other hand,
inhibit adenylyl cyclase leading to a decrease of cyclic adenosine monophosphate
(cAMP) (Figure 5)
(http://www.macalester.edu/~psych/whathap/UBNRP/Ahschizophrenia/Neurochemistry.h
tm.)

Localization of the dopamine receptors in the human brain could be observed in the
following figures 6,7 and 8 (http://www.acnp.org/g4/GN401000026/CH026.html)

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Figure 6. Representative false-color images of dopamine receptor mRNA
localization in the human striatum. In the human striatum, D1, D2, and D3 receptor
mRNAs are expressed at moderately high levels. D1 and D2 receptor mRNAs are
homogeneously distributed throughout the dorsal striatum and nucleus accumbens. On
the other hand, D3 receptor mRNA is expressed in a striking gradient, with prominent
labeling apparent in the accumbens and the ventral aspect of the putamen, and minimal
labeling in dorsal striatum. Unlike D1, D2 and D3 receptors, D4 and D5 receptors have
minimal levels of expression in the human striatum. These observations suggest that
while D1 and D2 receptors are likely involved in both motor and limbic functions
mediated in the striatum, the D3 receptor may have a uniquely limbic function in this
brain region.

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Figure 7. Representative false-color images of dopamine receptor mRNA
localization in human neocortex (Brodmann area 17). All five dopamine receptor
transcripts are seen throughout the human neocortex. In prefrontal and temporal cortices,
the mRNAs encoding the D1 and D4 receptors are the most abundant of the five receptor
transcripts.

Figure 8. Representative false-color images of dopamine receptor mRNA

localization in the human midbrain at the level of the substantia nigra (SN). Also shown
is a representative section labeled for tyrosine hydroxylase (TH) mRNA, reflecting
dopamine synthesis. The dopamine receptor transcripts encode receptors that function as
autoreceptors. The midbrain dopamine cell groups consist of discrete zones of cells that
synthesize dopamine. The primary cell groups are the retrorubral fields, the pars
compacta of the substantia nigra and the ventral tegmental area. Dopamine receptors are
also expressed in these structures. Given that these receptors are located in cells that are
also synthesizing dopamine, they represent dopamine autoreceptors. The primary
dopamine receptor transcript that is identifiable in the human substantia nigra is D2
mRNA.

It is believed that positive symptoms of schizophrenia are associated with increased

activity at dopaminergic D2 receptor sites in the mesolimbic and mesocortical
pathways (Figure 9).

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Schizophrenia Symptoms

The characteristic symptoms of schizophrenia have often been conceptualized as falling

into three categories:

I. Positive Symptoms

 Hallucinations are disturbances of perception that are common in people

suffering from schizophrenia. Hallucinations are perceptions that occur without
connection to an appropriate source. Although hallucinations can occur in any
sensory form – auditory (sound), visual (sight), tactile (touch), gustatory (taste),
and olfactory (smell) – hearing voices that other people do not hear is the most
common type of hallucination in schizophrenia. Voices may describe the patient’s
activities, carry on a conversation, warn of impending dangers, or even issue
orders to the individual.
 Delusions are false personal beliefs that are not subject to reason or contradictory
evidence and are not explained by a person’s usual cultural concepts. Delusions
may take on different themes. For example, patients suffering from paranoid-type
symptoms – roughly one-third of people with schizophrenia – often have
delusions of persecution, or false and irrational beliefs that they are being cheated,
harassed, poisoned, or conspired against. These patients may believe that they, or
a member of the family or someone close to them, are the focus of this
persecution. In addition, delusions of grandeur, in which a person may believe he
or she is a famous or important figure, may occur in schizophrenia. Sometimes
the delusions experienced by people with schizophrenia are quite bizarre; for
instance, believing that a neighbor is controlling their behavior with magnetic
waves; that people on television are directing special messages to them; or that
their thoughts are being broadcast aloud to others.

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II. Disorganized symptoms:

 Disordered Speech, Thought Disorder, Disorganized Behavior and poor

attention. Schizophrenia often affects a person’s ability to “think straight.”
Thoughts may come and go rapidly; the person may not be able to concentrate on
one thought for very long and may be easily distracted, unable to focus attention.
People with schizophrenia may not be able to sort out what is relevant and what is
not relevant to a situation. The person may be unable to connect thoughts into
logical sequences, with thoughts becoming disorganized and fragmented. This
lack of logical continuity of thought, termed “thought disorder,” can make
conversation very difficult and may contribute to social isolation. If people cannot
make sense of what an individual is saying, they are likely to become
uncomfortable and tend to leave that person alone.

III. Negative Symptoms

 Restricted Range and Intensity of Emotional Expression. People with

schizophrenia often show “blunted” or “flat” affect. This refers to a severe
reduction in emotional expressiveness. A person with schizophrenia may not show
the signs of normal emotion, perhaps may speak in a monotonous voice, have
diminished facial expressions, and appear extremely apathetic. The person may
withdraw socially, avoiding contact with others; and when forced to interact, he or
she may have nothing to say, reflecting “impoverished thought.” (alogia)
Motivation can be greatly decreased, as can interest in or enjoyment of life.
(anhedonia) In some severe cases, a person can spend entire days doing nothing
at all, even neglecting basic hygiene. These problems with emotional expression
and motivation, which may be extremely troubling to family members and
friends, are symptoms of schizophrenia – not character flaws or personal
weaknesses.

Schizophrenia Subtypes

According to DSM-IV, subtypes of schizophrenia are defined by the predominant

symptoms at the time of the most recent evaluation and therefore may change over time.
These subtypes include:

 Paranoid type: in which preoccupation with delusions or auditory hallucinations

is prominent;
 Disorganized type in which disorganized speech and behavior and flat or
inappropriate affect are prominent
 Catatonic type, in which characteristic motor symptoms are prominent
 Undifferentiated type which is a nonspecific category used when none of the
other subtype features are predominant; and

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 Residual type where there is an absence of prominent positive symptoms but
continuing evidence of disturbance (e.g., negative symptoms or positive symptoms in an
attenuated form)
Pharmacologic Treatments

Drugs are used for the treatment of acute episodes, the prevention of future episodes, and
improvement of symptoms between episodes. Antipsychotic medications reduce the risk
of future psychotic episodes in patients who have recovered from an acute episode. Even
with continued drug treatment, some people who have recovered will suffer relapses. Far
higher relapse rates are seen when medication is discontinued. In most cases, it would not
be accurate to say that continued drug treatment “prevents” relapses; rather, it reduces
their intensity and frequency.

Antipsychotic drugs are classified as Typical and Atypical Antipsychotics. The typical
antipsychotic medications are equally effective in the treatment of psychotic
symptoms of schizophrenia although they vary in potency and their propensity to
induce side effects.

Typical Antipsychotics

Antipsychotic medication has been the mainstay of treatment for schizophrenia since
chlorpromazine was introduced in 1952. Many conventional antipsychotic drugs are
available, each differing in potency and side effects but similar in mode of action and
efficacy (Table 1). Typical antipsychotics are usually classified according to their
antipsychotic potency into:
.
"High Potency" agents (eg, haloperidol, fluphenazine, trifluoperazine), administered at a
low daily dosage and induce more EPS but cause less sedation, less anticholinergic side
effects and less postural hypotension than low potency drugs and,

"Low Potency" agents (eg, chlorpromazine, thioridazine), conversely used at high daily
dosages, cause more sedation, more anticholinergic side effects and more hypotension,
but induce fewer EPS than high potency drugs.48

Because the efficacy of these agents is similar, the choice of conventional antipsychotic
agent is generally based on side effect profile, patient tolerance, and the patient's previous
response.

Typical antipsychotic drugs usefulness in schizophrenia is due to dopaminergic D2

blockade in the mesolimbic and mesocortical pathways. They bind with very high
affinity and stay on the receptor, blocking the effects of dopamine for a very long time
-- long past the usual dosing interval (once or twice daily) of these drugs. In doing so,
they really shut down the postsynaptic cell and neural pathway because psychosis
involves an overstimulation of the dopamine system.

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Side effects

Common side effects.

Sedation is the most common single side effect of antipsychotic medications. It may
result from the histaminergic blockade (Table 2). Most patients experience some
sedation, particularly with the low-potency agents, such as chlorpromazine. Sedation is
most pronounced in the initial phases of treatment. Most patients develop some
tolerance to the sedating effects with continued administration. For agitated patients,
the sedating effects of these medications in the initial phase of treatment can have
therapeutic benefits. However, when sedation persists into maintenance treatment,
causing daytime drowsiness, it becomes a problem. Drowsiness may affect
performance of skilled tasks e.g. driving or operating machinery. Lowering of the
daily dose, consolidation of divided doses into one evening dose, or changing to a less
sedating antipsychotic medication can be helpful.

Anticholinergic and antiadrenergic effects. The anticholinergic effects of antipsychotic

medications (along with the effects of anticholinergic antiparkinsonian medications when
concurrently administered) can produce a variety of adverse effects, including dryness of
mouth, blurring of vision, constipation, tachycardia, and urinary retention. Of the
typical agents, the low-potency phenothiazines (which are highly anticholinergic) are
most likely to induce anticholinergic side effects. These side effects can be particularly
troublesome for older people. Co-existing diseases and conditions, such as
gastrointestinal disease, bladder neck obstruction, glaucoma, and cardiac disease, also
place patients at risk, and use of drugs with anticholinergic side effects should generally
be avoided. Although most of these effects are mild and tolerable, serious consequences
can occur. For example, death can result from ileus of the bowel if not detected in time.
In addition, some patients experience problems with thermoregulation and can develop
hyperthermia, particularly in warm weather.

Central anticholinergic toxicity can lead to impaired memory and cognition,

confusion, delirium, somnolence, and hallucinations. These symptoms can affect the
patient's response to psychosocial or rehabilitation programs and may impair the
individual's efforts to become reintegrated into the community. Such symptoms are more
likely to occur with medications that have more potent anticholinergic effects and in
elderly or medically debilitated patients. Cessation of treatment usually results in
reversal of symptoms.

Tachycardia can result from the anticholinergic effects of antipsychotic medications

but may also occur as a result of postural hypotension (reflex tachycardia).
Hypotension is caused by the antiadrenergic effects of antipsychotic medications.
When this is severe it can lead to syncopal episodes. Patients who experience severe
postural hypotension must be cautioned against getting up quickly and without assistance.
The elderly are particularly prone to this adverse effect, and syncopal episodes may
contribute to an increased incidence of hip fractures in elderly women.

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Extrapyramidal Side Effects (EPS). Of the spectrum of adverse effects of antipsychotic
medications, the neurologic side effects are the most troublesome (Table3).
Extrapyramidal side effects can broadly be divided into acute and chronic categories.

Acute extrapyramidal side effects are signs and symptoms that occur in the first days
and weeks of antipsychotic medication administration, are dose-dependent, and are
reversible upon medication dose reduction or discontinuation.

There are four types of acute extrapyramidal side effects: parkinsonism, dystonia, and
akathisia, which are quite common, and neuroleptic malignant syndrome, which
occurs infrequently but is potentially life threatening.

Parkinsonism. Medication-induced parkinsonism, characterized by the symptoms of

idiopathic Parkinson's disease (rigidity, tremor, akinesia, and bradykinesia), has been
found in 20% of patients treated with antipsychotics. Akinesia or bradykinesia is a
feature of medication-induced parkinsonism; a patient with this condition appears to be
slow moving, indifferent to stimuli, and emotionally constricted. Parkinsonian side
effects usually respond to a reduction in antipsychotic medication dose (if this can be
done while preserving the antipsychotic effects of treatment) or treatment with
antiparkinsonian medication (Table 3). Because of concern about exacerbating psychotic
symptoms, the traditional dopamimetic medication for parkinsonian symptoms (L-dopa)
is generally not used to treat medication-induced parkinsonism. Instead,
anticholinergic antiparkinsonian medications are the treatment of choice. In
addition to anticholinergic antiparkinsonian medications, weak dopamimetic medications,
such as amantadine, can be used as second-line or additional treatments. The efficacy of
these medications is good, but some patients who improve with antiparkinsonian
medication continue to have residual parkinsonian symptoms.

Acute dystonia is characterized by the spastic contraction of discrete muscle groups.

Dystonic reactions occur in 10% of patients initiating therapy. Risk factors include young
age, male gender, use of high-potency medications, high doses, and intramuscular
administration. They can occur in various body regions but most commonly affect the
neck, eyes, and torso. The specific name of the reaction is derived from the specific
anatomic region that is affected. Hence, the terms "torticollis," "laryngospasm,"
"oculogyric crisis," and "opisthotonos" are used to describe dystonic reactions in
specific body regions. These reactions are sudden in onset, are dramatic in appearance,
and can cause patients great distress. For some patients these conditions, e.g.,
laryngospasm, can be dangerous and even life threatening. Acute dystonic reactions
respond dramatically to the administration of anticholinergic (Table 3) or
antihistaminic medication, usually given parenterally (intramuscularly or
intravenously). Afterwards, these patients are usually maintained with an oral regimen of
anticholinergic antiparkinsonian medication to prevent the recurrence of acute dystonic
reactions.

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Akathisia is characterized by somatic restlessness that is manifest subjectively and
objectively in 20%-25% of patients treated with antipsychotics. Patients
characteristically complain of an inner sensation of restlessness and an irresistible
urge to move various parts of their bodies. Objectively, this appears as increased motor
activity. The most common form involves pacing and an inability to sit still. This side
effect is often extremely distressing to patients, is a frequent cause of noncompliance
with antipsychotic treatment, and, if allowed to persist, can produce dysphoria and
possibly aggressive or suicidal behavior. Akathisia is less responsive to treatment than are
parkinsonism and dystonia. A first step that may improve akathisia symptoms is a small,
slow reduction in antipsychotic dose. Anticholinergic antiparkinsonian medications
have limited efficacy but are usually the first line of treatment (see Table 3),
particularly if the patient also has another extrapyramidal side effect.

Benzodiazepines can also be used to treat akathisia. Lorazepam and clonazepam are the
most commonly used, but most benzodiazepines may be beneficial.

Prophylactic treatment. Given the high rate of acute extrapyramidal side effects among
patients receiving antipsychotic medications, the prophylactic use of antiparkinsonian
medications may be considered. The various medications used to treat acute
extrapyramidal side effects are listed in Table 4. The major differences among the
anticholinergic medications are in their potencies and durations of action. Patients who
are very sensitive to anticholinergic side effects (e.g., dry mouth, blurred vision,
constipation) may require lower doses or less potent preparations (e.g., trihexyphenidyl,
procyclidine hydrochloride).

Neuroleptic malignant syndrome. Neuroleptic malignant syndrome is characterized by

the triad of rigidity, hyperthermia, and autonomic instability, including hypertension
and tachycardia and it is often associated with elevated serum creatine kinase activity.
This condition can be sudden and unpredictable in its onset, is frequently misdiagnosed,
and can be fatal in 5%-20% of cases if untreated. The first step in treatment is to
discontinue the antipsychotic medication; then supportive treatment for the fever or
cardiovascular symptoms should be provided. Treatments that have been used to
accelerate the reversal of the condition include dopamine agonists, such as bromocriptine,
pergolide, and lisuride, and antispasticity agents, such as dantrolene sodium

Chronic extrapyramidal side effects are signs and symptoms that occur after months
and years of antipsychotic medication administration, are not clearly dose
dependent, and may persist after medication discontinuation. Tardive dyskinesia is
a hyperkinetic abnormal involuntary movement disorder caused by sustained
exposure to antipsychotic medication that can affect neuromuscular function in any body
region but is most commonly seen in the oral-facial. Various factors are associated with
greater vulnerability to tardive dyskinesia. Schizophrenia itself may be associated with a
risk of spontaneous dyskinesia indistinguishable from medication-induced tardive
dyskinesia Other risk factors include older age, female gender combined with
postmenopausal status, diagnosis of affective disorder (particularly major depressive
disorder), concurrent general medical disease such as diabetes, and use of high doses of

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antipsychotic medications Discontinuation of medication should be considered only if
the patient is in full remission or very stable with few residual positive symptoms or if the
patient insists on stopping medication. The options include dose reduction and switching
to a newer antipsychotic medication. The dose can gradually (over 12 weeks) be reduced
by 50%. However, if the symptoms are severe or distressing to the patient, treatment for
the tardive dyskinesia should be considered. Anticholinergic drugs may worsen
condition once symptoms are present.

Other side effects.

Seizures. Antipsychotic medications can lower the seizure threshold and result in the
development of generalized grand mal seizures. Among the typical antipsychotics, the
low-potency conventional antipsychotics confer the greatest risk The frequency of
seizures is dose related, with higher doses associated with greater risk. Patients with a
history of an idiopathic or medication-induced seizure have a higher risk. If a patient
experiences a seizure, antipsychotic medication should be withdrawn or the dose reduced
by 50% until a neurologic evaluation is completed.

Galactorrhea and oligomenorrhea. All standard antipsychotic medications increase

prolactin secretion due to its D2 antagonistic activity in the tuberoinfundibular tract of the
hypothalamus antipsychotics. There they reverse the tonic dopaminergic inhibition of
prolactin in the anterior pituitary (Figure 10). The resultant hyperprolactinemia can lead
to galactorrhea in 1% to 5% of patients and menstrual cycle changes (e.g.,
oligomenorrhea) in up to 20% of women. Reduction in medication dose may decrease the
severity or alleviate these effects. When the antipsychotic dose must be maintained and
galactorrhea is severe or for women with menstrual disturbances, low doses of
bromocriptine or amantadine may be used.

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Weight gain. Weight gain occurs with most antipsychotic medications in up to 40% of
treated patients. The dose of antipsychotic medication may be reduced and efforts at
dietary control initiated.

Effects on sexual function. These include: erectile dysfunction, ejaculatory disturbances

in men and loss of libido or anorgasmia in women and men. These effects are mainly due
to antiadrenergic and antiserotonergic effects. Sexual dysfunction can be a problem,
sometimes linked to drug-induced hyperprolactinaemia. It is likely to be an
underreported side effect of antipsychotic treatment, as discussion of this issue is often
difficult to initiate. Dose reduction or discontinuation usually results in improvement or
elimination of symptoms.

Allergic and hepatic effects. Cutaneous reactions occur infrequently with antipsychotic
medications. Medication discontinuation or administration of an antihistamine is usually
effective in reversing these symptoms. Photosensitivity also occurs infrequently and is
most common with the low-potency phenothiazine medications; patients should be
instructed to avoid excessive sunlight and/or use sunscreen. Also occurring with this class
of medications are elevation of liver enzyme levels and cholestatic jaundice. This usually
occurs within the first month after the initiation of treatment and generally requires
discontinuation of treatment. Given the relative infrequency of antipsychotic-induced
jaundice, other etiologies for jaundice should be evaluated before the cause is judged to
be antipsychotic medication.

Ophthalmologic effects Pigmentary retinopathies and corneal opacities can occur with
chronic administration of the low-potency medications thioridazine and chlorpromazine,
particularly at high doses For this reason, patients maintained with these medications
should have periodic ophthalmologic examinations With the increased use of high-
potency medications in the past two decades, there has been virtually no reporting of this
side effect

Hematologic effects. Hematologic effects, including inhibition of leukopoiesis, can

occur with use of antipsychotic medications. Such effects include a benign leukopenia
and the more serious agranulocytosis.

Serotonin

Serotonin was discovered in the late 1940s, and within a decade there were indications
for its existence in the central nervous system of animals and for a neurotransmitter
function. It is a monoamine neurotransmitter found in cardiovascular tissue, the
peripheral nervous system, blood cells, and the central nervous system. In the CNS, the
cell bodies for serotonergic neurons are found in the raphe region in the
brainstem/pons region. Serotonin also serves as a precursor for melatonin production
in the pineal gland.

17
Serotonin synthesis

The biosynthesis of serotonin from the amino acid tryptophan is similar to that found for
the catecholamines, and 5-hydroxytryptophan can cross the Blood Brain Barrier to
increase central levels of 5-HT (Figure 11).

Although serotonin is metabolized by monoamine oxidase to 5-hydroxyindoleacetic acid,

most of the serotonin released into the post-synaptic space is removed by the neuron
through a reuptake mechanism.

Serotonin Pathways

The distribution of neurons, containing 5-HT is very widespread. The cells occur in
several large clusters in the pons and upper medulla, which lie close to the midline
(raphe) and are often referred to as raphe nuclei. The rostrally situated nuclei project, via
the medial forebrain bundle, to many parts of the cortex, hippocampus, basal ganglia,
limbic system and hypothalamus. The caudally situated cells project to the cerebellum,
medulla and spinal cord (Figure 12).

18
Serotonin receptors
Serotonin receptors are diverse and numerous. Over the past decade, more than 14
different serotonin receptors have been cloned through molecular biological techniques.
These studies have helped identify new therapeutic targets, and aided an understanding of
the multiple roles played by 5-HT in the brain. Overall, seven distinct families of 5-HT
receptors have been identified, with as many as five within a given family. Only one of
the 5-HT receptors (5-HT3) is a ligand-gated ion channel; the other six belong to the G
protein-coupled receptor family.

5-HT1A receptors are found in the hippocampus, cerebral cortex, raphe nuclei, thalamus
and amygdala. 5-HT1A receptors may be autoreceptors that regulate serotonin release.
Within the 5HT1 group there are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E, and 5HT1F.
There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C as well as two 5HT 5 subtypes,
5HT5a and 5HT5B. Antipsychotic actions of atypical antipsychotics are mainly
mediated by their interactions with serotonin receptors 5-HT2 receptors blockade.

The Serotonin Theory of Schizophrenia

Though there is no clear biochemical evidence suggesting any alteration in 5-HT

metabolism or 5-HT receptor function in schizophrenia, many effective antipsychotic
drugs, in addition to blocking DA-receptor also act as 5-HT2 receptor antagonists. 5-HT
has a modulatory effect on DA pathways (Figure 13), so the two theories are not
incompatible.

19
 Serotonin-
Serotonin-Dopamine Interactions
Serotonin-Dopamine
Prefrontal Cortex Dopamine (DA)

GABA Serotonin (5-

(5-HT)
Glutamate Striatum
GABA/ACh
GABA/ACh Motor Outputs
Limbic
System Blockade of D2 receptors
by conventional APDs
causes EPS

Ventral Tegmental Area Substantia Nigra

(A10) (A9)

5-HT2A antagonists
Median Dorsal release dopamine from
Raphe Raphe inhibition
and decrease EPS

Anatomical and electrophysiological studies demonstrate that serotonergic neurons from

the dorsal and median raphe nuclei project to dopaminergic cell bodies within the Ventral
Tegmental Area and the Substantia Nigra of the midbrain. Serotonergic neurons
primarily from the dorsal raphe project to the terminal fields of the striatum, nucleus
accumbens and cortex. Serotonergic neurons have been reported to directly terminate on
dopaminergic cell bodies and exert an inhibitory influence on mesolimbic and
nigrostriatal dopamine activity through 5-HT2A receptors. In general, reductions in
serotonin activity are associated with enhancements in dopamine activity.

Atypical Antipsychotics

Over the past seven years, risperidone, olanzapine, quetiapine and ziprasidone ,
paliperidone, asenapine, iloperidone, and lurasidone have been added to the
pharmacotherapy of schizophrenia. Sertindole, another atypical antipsychotic, was found
to induce Q-T interval prolongation, and its manufacturer, Abbott Laboratories, withdrew
the drug from FDA review. The five new agents have broad brain receptor profiles and
differing affinity ratios for various receptors which determine their pharmacological
activity.
The second-generation drugs, which have lower affinity for the D2 receptor, bind to the
receptor in the same way that first-generation drugs do, but they stick to the receptor less
tightly and for a shorter period of time. They come loose from the receptor and allow for
its stimulation by dopamine sooner than would be the case with the earlier drugs, so there
is an intermittent attenuation or antagonism of dopaminergic stimulation of the D2
receptor. The activities of these drugs on the other neurotransmitter receptors do not seem
to be relevant to the therapeutic effects, but certainly may be relevant to the side effects
that these drugs produce, particularly the weight and metabolic side effects.

20
Clozapine

Clozapine is a dibenzodiazepine with weak D2 antagonist activity and high affinity

for D1 and D4; 5HT2; ; histamine and muscarinic receptors (Table 5). It was the
first atypical antipsychotic drug introduced. It is distinguished from typical antipsychotic
drugs by the lower incidence of acute extrapyramidal side effects with its use
compared to typical antipsychotics (Table 6). The interactions between serotonin and
dopamine particularly at the 5-HT2A receptor have been suggested to be responsible for
the efficacy of atypical antipsychotics and their low potencial to produce EPS (Figure
13).

There is also evidence that clozapine is less likely to cause tardive dyskinesia than other
antipsychotic medications and may be an effective treatment for tardive dyskinesia and
tardive dystonia (although clozapine is not a cure for tardive dyskinesia, it may allow
time for recovery from tardive dyskinesia in some patients). However, it causes
potentially fatal agranulocytosis in about 1% of patients. Agranulocytosis is defined as
a granulocyte count less than 500/mm3. Current guidelines specify that the WBC count
be checked before initiation of clozapine treatment, at least weekly for the duration of
treatment, and weekly for 4 weeks after the termination of treatment. Patients are
advised to report any sign of infection (e.g., sore throat, fever, weakness, or lethargy)
immediately. Agranulocytosis is usually reversible if treatment is discontinued
immediately. Patients with agranulocytosis should not receive clozapine again.

Other side effects include sedation, weight gain (see olanzapine), hypersalivation
(sialorrhea), tachycardia, orthostatic hypotension, and fever. The first three are
extremely common, occurring in the majority of patients, particularly in the initial phase
of treatment.
The pathophysiology of clozapine hypersalivation is not yet totally understood. The
following is a proposed mechanism. Clozapine has antagonistic effects at both 1- and
2-receptors. It is suggested that both subtypes of receptors are on the salivary glands,
where blockade causes an increase in blood flow, resulting in increases in salivary flow
and composition. Supporting this theory is that -methyldopa, an 2 agonist is effective
in treating clozapine hypersalivation. Another theory is that clozapine is a full agonist at
the M4 receptor in salivary glands leading to an increase in secretions. Agonism at the
M4 receptor may determine in part why sialorrhea does not occur with other atypical
anti-psychotics, especially those with -blockade.

The seizure risk for clozapine is dose-dependent and it is related to dose as well as rapid
increases in dose.

Risperidone

Risperidone was the second atypical to be introduced with the advantage of lacking the
agranulocytosis associated with clozapine. It is an antagonist of D2, D1, D4; 5HT2 and
 receptors. Studies using multiple doses of risperidone have shown that this
medication causes a dose-related increase in extrapyramidal side effects, however, the

21
severity of these side effects is lower than with typical antipsychotics. Risperidone
produces some drowsiness and orthostatic hypotension. Other common side effects
among patients treated with risperidone include weight gain decreased sexual interest
and erectile dysfunction. Risperidone elevates prolactin levels, and as a result it may
cause galactorrhea and menstrual disturbances. Several cases of neuroleptic malignant
syndrome associated with risperidone have also been described.

Olanzapine.

It is a thienobenzodiazepine. It is an antagonist of D2, D1 and D4; 5HT2; ;

histamine and muscarinic receptors. As we the above two atypical antipsychotics,
olanzapine appears to cause fewer extrapyramidal symptoms than typical
antipsychotics. The most common side effects of olanzapine are sedation and a
decrease in standing systolic blood pressure; Weight gain has been a problem with the
older agents and has been noted with the atypical antipsychotics as well. Weight gain
with atypical agents is associated with increased appetite, though the underlying
mechanism remains unclear. Some researchers believe that weight gain stems from 5HT2
receptor blockade, based on evidence that drugs that enhance serotonergic transmission
decrease carbohydrate intake, and on other evidence that cytoproheptadine (a
serotonergic blocker) increases appetite. Some theorize that sedation and a resulting
decrease in physical activity may contribute to lowered caloric expenditure.

Regardless of mechanism, significant weight gain (defined as greater than 7% of baseline

weight) has been reported in patients receiving atypical antipsychotics. Studies show that
weight gained is generally distributed centrally and that waist-hip ratio is increased. This
type of weight gain has been associated with greater health risk, especially in the cardiac
system. Generally, most weight gain occurs in the first year or two of treatment, then
reaches a plateau. Knowing that weight gain may occur with antipsychotic therapy should
prompt practitioners to monitor residents closely for the presence of comorbid conditions
such as diabetes or hypertension, as weight gain in these patients may be particularly
detrimental. Weight gain is one of the reasons of treatment non-adherence with
antipsychotics. Therefore, baseline weight, monthly weights and BMI should be
measured for all patients prescribed atypical antipsychotics. Nutritional intervention for
obese individuals (BMI =30), or those experiencing significant weight gain (=7%) should
be provided during treatment. Among the atypical olanzapine has been associated
with higher incidence of weight gain.

Clozapine and olanzapine are associated with the most significant increase in
triglyceride levels. A full lipid panel with fractionation of cholesterol should be
performed annually as part of routine health monitoring for inpatients and outpatients. A
baseline and then three monthly fasting total triglycerides and cholesterol should be
considered during the first year of atypical antipsychotic therapy. Similarly, treatment
with these two drugs is associated with the greatest increase in glucose levels. There are
only a few reports describing an association between diabetes mellitus and quetiapine or
risperidone though this may reflect the lower prescribing rate of these drugs. In most

22
instances, hyperglycaemia, (due to olanzapine or clozapine), is not dose dependent,
occurs between 10 days to 18 months after initiation of treatment, and is reversible on
cessation. A baseline and three monthly fasting glucose during the first year of therapy
for patients with schizophrenia should be obtained in those receiving atypical
antipyschotics. This may be reduced to six monthly if no changes in fasting glucose are
noted and if the individual lacks other risk factors All patients on any antipsychotic
should receive annual fasting glucose.
Aripiprazole
Aripiprazole typifies the third group of antipsychotic drugs. It is a partial D2 agonist that
binds to the D2 receptor with very high affinity. It sticks to the receptor a long time, but
has the ability to stimulate the receptor at a low level, at about 30% of the rate of
stimulation of dopamine (hence, the term "partial agonist"). This drug shuts down the cell
from overstimulation by dopamine, but it also stimulates it to some degree so that it's not
completely inactivated.
It is the least likely to produce negative effects on triglyceride or glucose levels. 5-
HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic
neurotransmission via activation of 5-HT2C receptors. This may be partly responsible for
the minimal weight gain associated with this drug.

Compliance

There are a variety of reasons why people with schizophrenia may not adhere to
treatment but these are the commonest:

 Patients may not believe they are ill and may deny the need for medication
 They may have such disorganized thinking that they cannot remember to take
their daily doses.
 Some patients report that side effects of the medications seem worse than the
illness itself.
Routes of administration.

Antipsychotics can be administered in oral forms, as short-acting intramuscular

preparations, or as long-acting depot preparations. Short-acting intramuscular
medications reach a peak concentration 30-60 minutes after the medication is
administered, whereas oral medications reach a peak in 2-3 hours. As a result, the
calming effect of the antipsychotic may begin more quickly when the medication is
administered parenterally. However, this calming effect on agitation is different from the
true antipsychotic effect of these medications, which may require several days or weeks.
Olanzapine and zyprasidone are available as short-acting injectable drugs.

Long-acting depot antipsychotic medications (fluphenazine decanoate or enanthate and

haloperidol decanoate) require at least 3 to 6 months to reach a steady state. As a result,
they are seldom used during acute treatment, when the psychiatrist is adjusting the dose
in accordance with therapeutic and side effects. Depot medications are thought to be

23
especially helpful in the maintenance phase. Very recently, risperidone was the first
atypipical antipsychotic available as depot.

Some famous people affected by schizophrenia

 Syd Barret (member of rock group Pink Floyd)
 Peter Green (founder of rock group Fleetwood Mac)
 Zelda Fitzgerald (painter and wife of Scott Fitzgerald)
 John Nash (mathematician and Nobel laureate)
 Vaslav Nijinsky (ballet dancer and choreographer)
 Brian Wilson (songwriter and member of the Beach Boys)

24
 Table 1. Selected Antipsychotic Drugs

Antipsychotic Drugs

Typical Antipsychotics

 Phenothiazines
Chlorpromazine
Thioridazine
Fluphenazine
Trifluoperazine

 Butyrophenones
Haloperidol

Atypical Antipsychotics

 Clozapine (Clozaril)
 Risperidone (Risperdal)
 Olanzapine (Zyprexa)
 Quetiapine (Seroquel)
 Ziprasidone (Geodon)
 Aripiprazole (Abilify)

Table 2. Possible Effects of Receptor Blockade

Receptor Type Potential Therapeutic Effect Potential Adverse Effect

Dopamine Improvement in Type I Extrapyramidal symptoms,
(positive) symptoms elevated prolactin levels
Serotonin Improvement in Type II Altered food intake/appetite
(negative) symptoms
Histaminergic No known effect Drowsiness, somnolence
-Adrenergic No known effect Orthostatic hypotension
Muscarinic No known effect Anticholinergic effects (dry mouth,
constipation, urinary retention, etc.)

Table 4. Selected Drugs for Treating Acute Extrapyramidal Side Effects

25
 Some Remarks Duration of Frequency
Drug
Action (Hrs) (times/day)

Trihexyphenidyl (Artane) Least Sedating

6-12 2-3

Benztropine mesylate Longest duration of action

(Congentin) and can be used once or
24 1-2
Oral and Parenteral twice a day
preparations

Biperiden hydrochloride
(Akineton)
6-12 2-4
Oral and Parenteral
preparations

Lower incidence of memory

loss and other central as well
as peripheral anticholinergic
Amantadine (Symmetrel) 12
side effects but it may
occasionally exacerbate
schizophrenic symptoms

Table 5. Comparison of Selected Antipsychotic Drugs

Drug Trade Name Extrapyramidal Sedation Anticholinergic Orthostatic

Symptoms Activity Hypotension
Chlorpromazine Thorazine Moderate High High High
Clozapine Clozaril Very low High Very high High
Fluphenazine Prolixin, Permitil Very high Moderate Moderate Moderate
Haloperidol Haldol Very high Moderate Moderate Moderate
Olanzapine Zyprexa Very low Low Low Very low
Risperidone Risperdal Varies Low Low High
Thioridazine Mellaril High Moderate Moderate Moderate
Trifluoperazine Stelazine High Low Low Low

Table 6 . Comparison of Atypical Antipsychotic Drugs

26
Drug Receptor Affinity Adverse Effects

Agranulocytosis
Sedation
Weight gain
D1, D4, 5-HT2, ,
Clozapine (Clozaril) Hypersalivation
histamine and muscarinic
High risk for diabetes and elevated
Weak D2 antagonist
triglycerides
Tachycardia,
Orthostatic hypotension

Dose-related increase in extrapyramidal side

effects
Sedation
Orthostatic hypotension.
Risperidone (Risperdal) D2, D1, D4, 5-HT2 and 
Weight gain
Elevates prolactin levels,
Several cases of neuroleptic malignant
syndrome

Sedation
Orthostatic hypotension.
D2, D1, D4, 5-HT2, ,
Olanzapine (Zyprexa) Weight gain
histamine and muscarinic
Diabetes
Increase in triglyceride levels.

Appears to have lower significant risk for

Ziprasidone (Geodon) D2, D1, D4, 5-HT2 and . weight gain, high cholesterol levels, or
diabetes. May prolong QT interval

Partial agonist at D2, Full

agonist at D3, D4, Appears to have NO significant risk for high
Aripiprazole (Abilify)
Antagonist at 5-HT2A and cholesterol levels, or diabetes.
.

27
Pronunciation

1. Haloperidol (ha-loe-PER-i-dole)
2. Chlorpromazine ((klor proe' ma zeen)
3. Fluphenazine (floo fen' a zeen)
4. Trifluoperazine (trye floo oh per' a zeen)
5. Clozapine (KLOE-za-peen)
6. Risperidone (ris-PER-i-done)
7. Olanzapine (oh-LAN-za-peen )
8. Ziprasidone (zi pray' si done)

28