The Presentation I used to discuss my literature review on citalopram

1. By David Quilliam

2.  Studied two neurological
disorders this year
(Parkinsons Disease and
Schizophrenia)
 Give myself a wider
range of the drugs
involved in neurological
disorders
 I wanted a greater
understanding of drug
targets as I plan on
venturing into organic
drugs in medicinal
chemistry

3.  Citalopram goes under the brand names
Celexa and cipramil. Received FDA approval
in 1998.
 Citalopram is a widely used antidepressant. It
is most commonly used in the treatment of
major depressive disorder (MDD).
 It has a high selective serotonin reuptake
inhibitory action (SSRI) with a good safety
profile and good efficacy.

4.  Common mental illness
 It is associated with morbidity, poor quality of
life, and a high risk of suicide.
 Serious impacts on patients and their families.
 WHO predicts it will be the number one
disability in 2030 in both developed and
developing countries.
 Tricyclic antidepressants (TCA’s) can be used in
the treatment of MDD, selective reuptake
inhibitors are often used as the leading
antidepressant drug.

5. Two main symptoms associated with MDD.
 Anhedonia (inability to experience pleasure from
various activities e.g. exercise and hobbies),
 Reduced motivation.
Related to reduced activity of the mesolimbic
dopamine system. Because of this, it is believed
that the antidepressant drugs should increase the
release of neurotransmitters serotonin, dopamine
and even that of epinephrine. The aim is to do this
without causing side effects e.g. Dopamine in the
mesolimbic system – psychosis.

6.  MDD is not greatly understood, but the main theory
is that depression is strongly related to a reduction
in the activity of serotonergic neurons.
 Presynaptic and postsynaptic malfunctions in the
serotonin systems cause a lack of serotonin in
areas of brain, causing depression.
 However whilst serotonin is believed to play a large
factor, many other monoamine-based
neurotransmitters also appear to play a role in
depression.
Neurotransmitter deficiency Symptoms
Norepinephrine Reduced alertness, energy and attention
Serotonin Anxiety, obsessive and compulsive behaviours
Dopamine Diminished motivation and diminished
pleasure

7.  Citalopram works by inactivating serotonin
transporters.
 These prevent presynaptic reuptake, and
increases the synaptic extracellular
concentrations of serotonin.
 Increase in stimulation of all serotonin
receptors e.g. postsynaptic 5-HT1A receptors.
 Main mechanism of SSRI’s is an increase in
levels of serotonin, also inhibit reuptake of
other monoamines.
 The full mechanism however is not known.

9.  There is a delayed onset of action with these
antidepressant drugs, and this can cause an
increased duration of time that the
impairments associated with MDD can occur.
One of these impairments is an increased risk
of suicide.
 These antidepressants also have a delayed
onset of action, and usually take 4-6 weeks
to take full effect. The delayed onset of action
of citalopram is believed to be due to this
reduced 5HT1A receptor stimulation.

10.  The use of SSRI’s in the treatment of MDD has
a chance of giving a negative response.
Roughly 40-50% of patients suffering from
MDD do not show a positive response to
SSRI’s.

11.  Studies show that after a full remission of
MDD using citalopram, 90% of patients still
showed at least one residual symptom of
depression.
 Weight increase most common (71.3%)
 Mid-nocturnal insomnia (54.9%)
 Those who remitted within 6 weeks of
diagnosis showed to have fewer symptoms
than those who remitted later on.
 larger number of residual symptoms are at
more risk of relapse.

12.  28% of patients had discontinued treatment
by the end of the first month of their
treatment.
 Mostly believed to be due to delayed onset of
action

13.  SSRI’s in combination with a 5HTx antagonist is a potential
solution
 With 5HT2A antagonism, the 5HT1A postsynaptic receptor
stimulation and also the prevention of noradrenergic
dampening occurs. By improving both of these factors, the
efficacy of SSRI’s is increased. Pipamperone is a weak
neuroleptic drug that showed to decrease the amount of
patients that discontinued their treatment by 80%
 With 5HT2C antagonism, Dopamine is under tonic inhibition
in areas of the brain by 5-HT through stimulation of 5-
HT2C receptors which are located on either GABA-ergic
neurones or dopaminergic neurones. SB was used in this
study and showed an increase of dopamine in the VTA and
Nacc by over 500%

16.  Serotonin syndrome is a serious adverse
reaction that is thought to result from a
hyprestimultionof brainstem 5HT1A and 5HT2A
receptors.
 It is believed to be brought about by an
interaction of two different serotonin
reuptake inhibitors.
 This occurs with phenylpiperidine based
opioids e.g. pethidine, tramadol and fentanyl
are weak serotonin reuptake inhibitors.