Drugs for neurological disorders II

Psychosis, bipolar disorder and OCD

Dr. Judith C.W. Mak

Department of Pharmacology & Pharmacy

( L12, BBMS3014, Advanced Pharmacology)

 Learning outcomes
At the end of the lecture, students should be able to

• Understand the symptoms, forms and pathophysiology of

psychosis, bipolar disorder and obsessive compulsive
disorder (OCD)
• List the different classes of medications available
• Describe their mechanism of action for each class (type)
of drugs
• Recognize their side (adverse) effects including tolerance
and dependence
 What is OCD?
• An anxiety disorder characterized by unreasonable
thoughts and fears (obsessions) that lead you to do
repetitive behaviors (compulsions)
OCD cycle
 Symptoms of OCD
• Symptoms tend to come and go over time and can range from mild to
severe
• Anxiety is the most common symptom
• Obsessions: unwanted thoughts, ideas and impulses that the subject will
have again and again
– A fear of getting dirty or infected
– A need to do things perfectly or correctly
– A fear of harm to yourself or loved ones
• Compulsions: behaviors that the subject needs to repeat to try to control
the obsessions
– Washing or checking something that has been done over and over
– Repeating things or always moving things to keep them in perfect order
– Praying
– Hoarding
• Some people may understand that their obsessions and compulsions are
not real but other times they may not be sure, or they may believe strongly
in their fears
 What causes OCD?
• Genes: can run in the family
• Stress: in about one out of three
cases
• Life changes: sudden role
change – puberty, child birth,
new job etc.
• Brain changes: imbalance of a
chemical called serotonin
• Personality: obsessive,
perfectionist, high on morality
and responsibility
The areas of the brain affected in OCD
Obsessive-compulsive disorder
(OCD)
 Treatment of OCD I
• Treating OCD will depend on how much the condition is
affecting the person’s ability to function

• How much impact OCD has on a person’s life depends

on:
– The amount of time spent on a compulsive behavior or ritual
– The intensity of the behavior
– How much of it happens in their mind, rather than in their
actions
Treatment of OCD II
 Treatment of OCD III
• Psychotherapy
– Cognitive behavioral therapy (CBT)

• Medications
– Antidepressants e.g. fluoxetine (SSRIs)
– Anti-anxiety, e.g. clonazepam, lorazepam (BZs)
 What is CBT?
• To alter cognitive processes by increasing
self awareness, facilitate better self-
understanding, and improving self control by
developing more appropriate cognitive and
behavioral skills
The 4 phases of cognitive therapy
for OCD
 Medications
• Selective serotonin reuptake inhibitors (SSRIs) – first-
line treatment of OCD
– Fluoxetine (Prozac)
– Paroxetine
– Citalopram
– Escitalopram
– Sertraline
– Fluvoxamine

• Serotonin norepinephrine reuptake inhibitors (SNRIs)

– Venlafaxine
– Mirtazapine

• Tricyclic antidepresants (TCAs)

– Clomipramine (a tertiary amine)
Mental illness
 Psychosis
• Is a mental health problem that stops the
person from thinking clearly, telling the
difference between reality and their
imagination and acting in a normal way
 Treatment of mental illness
• Antidepressants and antipsychotics
– They are NOT interchangeable

Antidepressants Antipsychotics

Used to treat depressive disorders Main purpose to manage psychosis

e.g. depression, anxiety e.g. delusions, hallucinations,

disordered thoughts

Schizophrenia
Main purpose is to life a person’s and bipolar disorder
mood
Blocks dopamine, a chemical in the
brain that controls the reward-driven
learning
 Symptoms of psychosis
• Hallucinations
– Perceive something that does not exist in reality (feeling)
 Symptoms of psychosis
• Delusions
– Where a person believes things that, when examined
rationally, are not true

Believe your next door neighbor

is secretly planning to kill you.
You may refuse to be in the same room with them.

A cellphone is in
mind-control device.

Certain people have some imaginary power of authority.

They may think they are the president or have the power
to bring people back from the dead.
Paranoia is a common component of psychotic delusions
 Symptoms of psychosis

• Confused and disturbed thoughts

– Their speech may be rapid and
constant
– Their content of speech may be random
(switch from one topic to another in the
middle of a sentence)
– The train of thoughts may suddenly
stop, resulting in abrupt pause in
conversation or activity
 Symptoms of psychosis
• A lack of insight and self-awareness
– Affected individuals are totally unaware that they act in
strange ways or have hallucinations or delusions
– They are able to recognize behaviors of others

e.g. a person with psychosis who is

being treated in a psychiatric ward
may complain that all of their fellow
patients are mentally unwell while
they are perfectly normal.
Summary of symptoms
Differential diagnosis of new-
onset psychosis
 Causes of psychosis
• Psychological conditions (e.g. mental illness)

• General medical conditions

• Substances (e.g. alcohol and drugs)

 Psychological conditions
• Schizophrenia – a condition where people
may have repeated episodes of psychosis

• Bipolar disorder – a condition where mood

swing from one extreme to another. Period
of depression at times followed by periods
of feeling energetic, impulsive and happy
(manic).

• Severe stress or anxiety

• Lack of sleep

• Severe depression – feelings of extreme

sadness for a prolonged period
Clinical description of
schizophrenia
General medical conditions
• Metabolic disorders
– Vitamin B deficiency (e.g. B12)
– Hyponatremia (low sodium in the blood)
– Hepatic encephalopathy
– Uremia
– Hyperadrenalism
– Hyper- or hypothryoidism (severe)
– Acute intermittent porphyria
• Brain diseases
– Huntington’s disease
– Wilson’s disease
– Paraneoplastic encephalitis
– Encephalitis or other CNS infection (e.g. neurosyphillis)
– Tumor
– Stroke
 Substances such as alcohol or drugs
• Drinking large amounts of alcohol
• High on drugs

Regular cannabis users are 40% more

likely to develop a psychotic illness
than people who do not use the drug.
 Who is affected?
• Estimated that 1 in 100 people
have at least one episode of
psychosis at some point in their life

• Most cases of psychosis develop

during late teens (>15 yrs. old) or
during adulthood

• Cases affecting children under 15

are rare
How common is psychosis?
• In 2011 (US), antipsychotics were prescribed to 3.1
million Americans at a cost of $18.2 billion, a 13%
increase over the previous year

• Research in England suggests, 1 case in every 2000

• ~200,000 psychosis patients in Hong Kong, 1,300

new cases being received by the Hospital Authority
annually
 Repeated psychosis causes
physical damage to the brain

• People with a history of psychosis may have less

grey matter than unaffected individuals

• Grey matter is the part of the brain responsible for

processing thoughts
 Treatment options
• Antipsychotic drugs – help to relieve the symptoms of
psychosis

• Psychological therapies – help to address the underlying

cause of psychosis

• Social support

• Family therapy

• Self-help group
 Classification of antipsychotics

Both types do not cure schizophenia and bipolar disorders, but can
ameliorate the symptoms
 Typical antipsychotics (1st generation)

• Available since 1950s

• Effective against positive
symptoms but NOT negative
symptoms of psychosis

Chlorpromazine
Fluphenazine
Haloperidol
Thioridazine
Trifluoperazine
Pimozide
Sulpiride
 Dopamine plays an important
role in psychosis
• Dopamine – a neurotransmitter,
that the brain uses to transmit
information from one brain to
another
• Dopamine is associated with how
we feel something is significant,
important or interesting
• Relative excess of functional
activity of dopamine in specific
neuronal tracts in the brain
• Excess dopamine interrupts
specific pathways of the brain
responsible for some of its normal
functions such as memory,
emotion, social behavior and self-
awareness
The dopamine hypothesis
• Many antipsychotic drugs
block brain dopamine
receptors (especially D2
receptors)

• Dopamine agonists (e.g.

amphetamine, levodopa)
exacerbate psychosis

• An increased density of
dopamine receptors has
been detected in certain
brain regions of untreated
schizophrenics
 Dopamine receptors
Five different dopamine receptors (D1 to D5) have been characterized
Location of dopamine receptors in brain

• D2 the most concentrated

– Cortex, corpus striatum, limbic system, basal ganglia, pituitary gland,
hypothalamus
 Dopamine receptors

• Each dopamine receptor is

G-protein-coupled and
contains 7 transmembrane
domains

• D2 is linked to Gi protein

• D2 is negatively coupled to
adenylyl cyclase

• Leading to decrease in cAMP

Dopaminergic tracts in the brain
Dopaminergic and serotoninergic pathways
 Extrapyramidal symptoms
• Acute dystonia – hyperkinetic movement disorder,
intermittent, uncoordinated involuntary contractions of
the muscle of the face, tongue, neck, truck and
extremities

• Akathisia – motor restlessness; an inability to sit still

• Parkinsonism – muscle rigidity, tremor, cognitive

impairment

• Tardive dyskinesia – painless, repetitive movements of

the orofacial structures; tongue protrusion, lip smacking,
involuntary repetitive body movement
 Cause of high prolactin level
• Gynecomastia (swollen breasts)

• Galactorrhea (milk discharge)

• Decrease in follicle-stimulating
hormone (FSH) and luteinizing
hormone (LH) release

• Loss of libido

• Sexual dysfunction – no ovulation

and menstruation
 Side effects of typical antipsychotics

• Extrapyramidal symptoms
• Hyperprolactinemia symptoms
• Drowsiness
• Emesis (e.g. vomiting)

D2 receptor blockade at the chemoreceptor

trigger zone is responsible for emesis

These drugs are still commonly used partly because of

their low cost
 Neuroleptic malignant syndrome

• Drug causes temperature regulation center to

fail

• Medical emergency

• Patient’s temperature suddenly increases to

dangerous levels

• Occurs every 1 of every 500 patients treated

• Typically develop over a period of 1-3 days of

drug usage
 Other receptors
• In addition to blocking dopamine receptors, many
antipsychotics have various activities at the adrenergic,
muscarinic, histaminergic, and serotoninergic receptors

• Most of the newer atypical antipsychotics have higher

affinities for other receptors than the D2 receptor
 Atypical antipsychotics
• The second generation drugs have
a heterocyclic structure
Amisulpride
• Available since 1990s
Aripiprazole
• 5-HT2 receptor binding exceed Clozapine
their affinity for dopamine D2 Risperidone
receptors Olanzapine
• Have lower risk of extrapyramidal Quetiapine
side effects Paliperidone
• Treat both the negative and Ziprasidone
positive signs of psychosis
Side effects of atypical antipsychotics
• Increased risk of high blood sugar
• Increased risk of diabetes
• Elevated lipids and cholesterol
• Severe weight gain (obesity)
– Possibly due to the combined H1
and 5-HT2 blockade

• Extrapyramidal effects – e.g.

movement disorders
• Hyperprolactinemia
• Neuroleptic malignant syndrome
• Sudden death
Side effects of atypical antipsychotics

• Antagonism of 1-adrenergic receptors leads to

reflex tachycardia and postural hypotension

• Antagonism of muscarinic receptors can produce

anticholinergic symptoms, including hyperthermia,
tachycardia, mydriasis, dry mouth, constipation,
urinary retention

• Antagonism of histaminergic receptors primarily

results in sedation and slowness
Choice of antipsychotics
 Pharmacokinetics
• All antipsychotic drugs are readily absorbed
• Enter CNS and most other body tissues
• Bound extensively to plasma proteins
• Require metabolism by liver enzymes before
elimination
• Other drugs inhibit cytochrome P450 enzymes can
prolong the half-lives of antipsychotic drugs
• Metabolism is primarily through the cytochrome
P450 enzyme system, with isoenzymes 2D6, 1A2
3A4 accounting for the majority of the drug
metabolism
Permanent structural impacts
• Chronic treatment with antipsychotics affect the brain
at the structural levels

• Reduction of the grey matter volume in different brain

areas

• Death of neurons in the cerebral cortex

• Recent studies on monkeys have found the

administration of haloperidol or olanzapine for 2
years led to a significant overall shrinkage in brain
tissue, with lower glial cell counts, due to a decrease in
astrocytes and oligodendrocytes
 Withdrawal problems
• Tardive dyskinesia
• Nausea Blockade of dopaminergic receptors by
antipsychotics
• Emesis
• Anorexia
Increase number and sensitivity of
• Anxiety dopamine receptors

• Agitation
• Restlessness Super-sensitivity psychosis

• Insomnia
• Psychosis Not sure if this is a true withdrawal symptom or a relapse of
the underlying disorder
 Off-label use of antipsychotics
Treating non-psychotic disorders includes:
• Agitation, e.g. nervousness
• Various headache conditions
• Anxiety disorders
• To suppress hiccups
• Control various involuntary motor disorders, e.g. Tourette
syndrome, Huntington chorea
• Autism spectrum disorders Risperidone was recently approved by the
US FDA for the treatment of irritability in
• Alzheimer’s disease children and adolescents with autism
• Depression
• Dementia
Other uses of antipsychotics
• Antipsychotics are prescribed for conditions such as
mild mood disorders, everyday anxiety, insomnia &
mild emotional discomfort

• The original target population of antipsychotics are

patients with schizophrenia and bipolar disorder, is
actually quite small

• Starting in 2003, several antipsychotics have

received FDA approval for the use in combination
with antidepressants to treat severe depression
 Summary
• Atypical antipsychotics can be lifesaving for people
who have schizophrenia, bipolar disorder or severe
depression
 Bipolar disorder
• Bipolar disorder is a mental
illness that brings severe high
and low moods and changes in
sleep, energy, thinking, and
behavior

• Bipolar disorder is also known

as manic depression
Bipolar disorder
Types of bipolar disorder
• Bipolar disorder type I
– The classic form of the disease in which patients
have periodic episodes of mania and depression
(mixed episode)

• Bipolar disorder type II

– Is the form in which patients do not develop
severe mania but go through episodes of
hypomania that alternate with milder depression

• Rapid cycling bipolar disorder

– When patients exhibit >4 episodes of mania,
depression or mixed episodes in a 12-month
period
The depressed brain from PET scans
Dopamine hypothesis of mania
 Bipolar disorder
• Distinct episodes of mania and depression

• Impact of the illness is severe (relationship, career, self-esteem and

longevity)

• Comorbid anxiety disorders occur in about 50% of patients, and

concurrent alcohol or substance abuse or dependence is present in at
least 40%

• Peak onset of illness is usually in early adult life (late adolescence to

late 20s) and there is a strong genetic basis

• Aim of treatment is to prevent recurrence of manic or depressive

symptoms; prevent suicide
 Treatment options
• Acute manic or mixed episodes
– Severe: mood stabilizer plus antipsychotic
– Less ill: mood stabilizer or antipsychotic
– Breakthrough: add antipsychotic once mood stabilizer optimized
– Treatment resistant: add/change antipsychotic, clozapine

• Acute depression
– Psychotic: add antipsychotic

• Maintenance
– Persistent psychosis: use antipsychotic
– When needed to prevent recurrence: use antipsychotic
 Lithium chloride or carbonate

• Most common drug used for

bipolar disorder

• Prescribed usually for a

minimum of 6 months

• Strict compliance is a MUST!

• Regular blood tests are

performed to ensure that the
levels of lithium are not too
high or low
 Lithium
• Mechanism of action: still unknown
• May be due to:
– Modulation of glutamate receptor
– Inhibition of inositol phosphatases
– Inhibition of glycogen synthase kinase 3 (GSK-3)

• Little or no psychotropic effect in normal

individuals
 Glutamate hypothesis for bipolar
disorder
• Mania
– Too much glutamate in the space between neurons
• Depression
– Too little glutamate in the space between neurons

Action of Lithium
• Lithium changes the currents of glutamate receptors, e.g. GluR3
• Enhance glutamate uptake and decrease glutamate availability in
synapse
• Glutamate is an excitatory neurotransmitter and reduction could
exert an antimanic effect
• It acts to keep the amount of glutamate active between cells at a
stable, healthy levels, neither too much or too little
Inhibition of inositol phosphatases
Neurotransmitter
Acetylcholine
• Lithium inhibits inositol phosphate
Norepinephrine and inositol formation
Serotonin
Dopamine – IMPase = inositol monophosphatase
– IPPase = inositol polyphosphate 1-
phosphatase

• Depletes phosphatidylinositol
bisphosphate (PIP2)

• Causes decrease in inositol

triphosphate (IP3) & diacylglycerol
(DAG)
– IP3 releases Ca2+ from the ER
– DAG activates intracellular processes

• Reduces neurotransmission as no
second messenger activation
Inhibition of glycogen synthase kinase 3 (GSK-3)

• Lithium leads to the deactivation of GSK-3 enzyme, a

multifunctional protein kinase
Role of GSK-3 in bipolar disorder
Summary
 Lithium toxicity
• Lithium may turn into poison very quickly!
• Common side effects
– Diarrhea Long term effects
– Vomiting
• Thirst
– Drowsiness • Frequent urination
– Muscle weakness • Tremor
• Weight gain
– Lack of coordination • Edema (swelling)
– Tinnitus (ringing in the ears)
– Blurred vision
– Sedation Severe effects
– Aphasia (unable to speak)
• Convulsion
– Thyroid enlargement • Stupor
• Coma
 • Lithium is related to sodium

• It is important to maintain
hydrated

• Too little water will decrease

urination which can lead to lithium
building up

• Hot weather, exercise, vomiting

and diarrhea all increase water
loss. Important to drink plenty of
fluid during these events

• Do not start a salt-reduced diet while taking lithium. A low salt intake can
increase the level of lithium in the blood
• A high salt intake can also lower the level of lithium in the blood
 Other medications
• Antiepileptic drugs – used to control seizures, but they are also
effective in treating bipolar disorder
– Valproate
– Carbamazepine
– Clonazepam
– Lamotrigine

• Antipsychotic drugs – used to control psychosis, but also act as long-

term mood stabilizer
– Typical antipsychotics, e.g. chlorpromazine
– Atypical antipsychotics
• Aripiprazole
• Olanzapine
• Quetiapine
• Risperidone
• Ziprasidone
 References
Basic & Clinical Pharmacology by Katzung, Masters and
Trevor (McGraw-Hill, 12th Edition, 2012)

Goodman & Gilman’s The Pharmacological Basis of

Therapeutics by Brunton, Chabner and Knollman (McGraw-
Hill, 12th Edition, 2011)

Lippincott Illustrated Reviews: Pharmacology by Karen

Whalen (Lippincott William & Wilkins, 6th Edition, 2014)

Rang & Dale’s Pharmacology by Rang, Dale, Ritter, Flower

and Henderson (Churchill Livingstone, 7th Edition, 2012)
 References
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• Krishnan V & Nestler EJ. Animal models of depression: molecular

perspectives. Curr Top Behav Neurosci 2011; 7:121-147.

• Hoffman KL. New dimensions in the use of rodent behavioral tests

for novel drug discovery and development. Expert Opin Drug Discov
2016; 11:343-353.

• Matsui H. The use of fish models to study human neurological

disorders. Neurosci Res. 2017 Feb 16. [Epub ahead of print]

• Khan KM, Collier AD, Meshalkina DA, et al. Zebrafish models in

neuropsychopharmacology and CNS drug discovery. Br J
Pharmacol. 2017 Feb 20. [Epub ahead of print]
Thank you!

E-mail: judithmak@hku.hk