Antidepressants

*Foye's principle of medicinal chemistry

 Depression
 Depression is the most common of the affective disorders (defined as disorders of mood rather
than disturbances of thought or cognition); it may range from a very mild condition, bordering on
normality, to severe (psychotic) depression accompanied by hallucinations and delusions.
 Worldwide, depression is a major cause of disability and premature death.
 In addition to the significant suicide risk, depressed individuals are more likely to die from other
causes, such as heart disease or cancer.
 The symptoms of depression include emotional and biological components.
 Emotional symptoms:
 misery, apathy (lack of interest in anything) and pessimism (tendency to expect worst)
 low self-esteem (confidence in your own merit as an individual person): feelings of guilt, inadequacy and ugliness
 Indecisiveness (unable to decide), loss of motivation.
 Biological symptoms:
 retardation of thought and action
 loss of libido (sex drive)
 sleep disturbance and loss of appetite.
 Two types of mood disorders
1) Unipolar disorders
– Depression – lacking enthusiasm
– Mania – excessive or unreasonable enthusiasm
2) Bipolar disorder (Alteration between manic-depressive phase)
 What does CLINICAL Depression feel
like?
Confessions of depressed people
“an empty hole (in ur heart)”
“ life not being worth anything”
“don’t feel sad or happy, feel numb”
“can’t make simple decision, can’t communicate”
“feels tiring”
“like the whole world is in your shoulder”
 How severe can depression be
physiologically?
• Depression isn’t just a psychological state that can drive to suicide. It has
physiological consequences too that can interfere with quality of life
• Insomnia (lack of sleep)
– Weakens immune system, fatigue
• Increases pain perception
• To suppress depression people do
– Excessive eating  obesity related heart problem
– Excessive alcohol  liver damage and withdrawal symptoms
 Cause of Depression
 The exact cause is unknown
 Monoamine Hypothesis : The accepted cause is deficiency of Neuro transmission by
biological amines
 Nor-adrenaline (NE)
 Dopamine (DA) and
 Serotonin(5HT) in the CNS

 Evidence – Reserpine, which has antihypertensive actions due to its ability to deplete
catecholamines (DA and NE) and 5HT from peripheral sympathetic nerve endings,
caused depression

 However not all monoamine reuptake inhibitors are anti-depressant eg Cocaine is a

potent inhibitor of noradrenaline and dopamine reuptake. However it is not an anti-
depressant but an addictive.

 Drugs that promote catecholamines and serotonin in the synapse relieved depression
 MAOI – block metabolism of DA and NE
 TCA – block reuptake of NE and 5HT
Perseverance : determined continuation with something
Obsess: never stop thinking about something
Intuition :something known or believed instinctively (natural), without actual evidence for it.
 Neurotransmitters and associated
Neuropsychiatric diseases

• Regulation of neurotransmitters is altered in a variety of psychiatric disorders

Neurotransmitters Diseases

Acetylcholine (ACh) Alzheimer’s disease

Serotonin Depression
Migraine, Aging
Attention deficit disorder (ADD)
Anxiety
Dopamine (High) Schizophrenia
(Low) Parkinsonism
GABA (γ-Aminobutyrate) Epileptic seizures

Glutamate Migraine
Stroke
Autism
 History of antidepressants
 MAOIs and tricyclics were the first antidepressants developed, dating back to the 1950s.
 These drugs came with numerous side effects and sometimes strict regiments for taking
the drugs.

 Because of this, researchers looked for an

alternative with similar effectiveness but
fewer side effects and found this in SSRIs.

 Even more recently,

researchers have
developed another class
of drugs, serotonin-
norepinephrine reuptake
inhibitors (SNRIs),
thought to be even more
effective but with similar
side effects to SSRIs.

https://antidepression.wordpress.com/2008/10/22/history-of-antidepressants/
 History of antidepressants
 One of these hypotheses is termed ‘the monoamine hypothesis’. This involves the monoamine
neurotransmitters, namely serotonin, norepinephrine, and dopamine, and suggests that depression is the
result in a deficiency in the levels or function of these monoamines in the brain. Treatment with reserpine,
a drug used for the control of high blood pressure, is often cited by purveyors of this hypothesis, as it is
associated with depression and also a drop in levels of monoamine neurotransmitters. This evidence is still
contested, however, and a number of studies have not found any difference in monoamine levels or
function in patients with depression. Whilst this doesn’t rule out their involvement entirely, it suggests
other factors may be at play.
 Another hypothesis involves neurotrophins, proteins responsible for development and function of neurons
in the brain. More specifically, it implicates Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin
responsible for the creation of neurons. Stress and pain are associated with a drop in levels of BDNF. Direct
injection of BDNF has been shown to have an antidepressant effect in animal models, and all known
antidepressants are also associated with an increase of BDNF. Again, however, not all evidence is in favour.
Animals bred to have a deficiency of BDNF have not exhibited the depression and anxiety that would be
expected.
 Further systems in the body have also been implicated – for example, the endocrine (hormone) system.
There is both supporting and conflicting evidence for each of the hypotheses, so it’s entirely possible that
they are not mutually exclusive, and could co-exist as factors in depression.
 Antidepressants can act in a number of ways, and considering the complex nature of depression, it’s
unsurprising that there’s no single unifying mode of action. However, they do all impact on the monoamine
neurotransmitters in some way; it is the manner in which they do this that varies. The precise role of the
monoamines in depression may be unclear, but we do have an idea of their specific roles as
neurotransmitters.
 History of antidepressants
 Serotonin is thought to be a contributor to feelings of well-being and happiness, as well as its other roles in
sleep regulation, and regulation of intestinal movements in the body. Norepinephrine’s roles include
attention and responding actions in the brain, and it is also involved along with epinephrine (adrenaline) in
the ‘flight or fight’ response. Finally, dopamine is associated with feelings of pleasure and satisfaction, and
is often termed as the brain’s ‘reward chemical’. All three of these chemicals in our brains can be affected
by antidepressants.
 The first class of ‘modern’ antidepressants to be discovered were the Monoamine Oxidase Inhibitors
(MAOIs), which work by inhibiting an enzyme that breaks down the monoamine neurotransmitters, thus
increasing their levels in the brain. These are now rarely used, as their toxicity is relatively high, and they
have significant side effects. However, they can still be used if depression is unresponsive to other
treatments.
 The majority of other antidepressants work by inhibiting the ‘reuptake’ of the monoamine
neurotransmitters in some way. Once neurotransmitters have performed their function of transmitting
signals in the brain, they are removed by absorption by proteins. Many antidepressants work by preventing
this removal, leading to increased levels of the neurotransmitter in the brain. Some antidepressants, such
as Selective Serotonin Reuptake Inhibitors (SSRIs) affect only a single neurotransmitter – in this case,
serotonin. Others affect noradrenaline and dopamine too.
 The SSRIs, which include drugs such as Prozac and Zoloft, are currently the most commonly used
antidepressants. This is largely due to the fact that a very high dose is required for toxic effects to be seen,
and the side effects are mild compared to other antidepressants. These side effects can, however, include a
reduced sexual desire; this is an effect common to the majority of antidepressants, with only a select few,
such as bupropion, avoiding it.
 Antidepressants are amongst the most widely used drugs – a survey by the Center for Disease Control &
Prevention in 2007 found that they were the most commonly prescribed drugs in the US in 2007. In 2010,
over 33 million prescriptions were written for Zoloft. It’s not just depression that they can be used to treat
– they also find applications in panic disorder, generalised anxiety disorder, post-traumatic stress disorder
(PTSD) and obsessive-compulsive disorder (OCD).

http://www.compoundchem.com/2015/01/20/antidepressants/
History of antidepressants
 Chemistry of Antidepressants
A variety of different chemical structures have been found to
have antidepressant activity.
A. Tricyclic antidepressants (TCAs):
Tricyclic antidepressants-so called because of the characteristic
three-ring nucleus. They closely resemble the phenothiazines
chemically and to a lesser extent, pharmacologically.

R1 : - (CH2)3N(CH3)2 R1 : =CH(CH2)2N(CH3)2
R2 : H Amitriptyline
R1: =CH(CH2)2NHCH3
Imipramine
Nortriptyline
 Chemistry of Antidepressants
B. Heterocyclics; second and third generation drugs:
Between 1980 and 1996, a number of heterocyclic agents denoted as second
generation and third generation or heterocyclic antidepressants were
introduced.
Second generation agents: Amoxapine, maprotiline, trazodone, bupropion
etc. Amoxapine and maprotiline resemble the structure of the tricyclic agents,
while trazodone and bupropion are distinctive.
Third generation agents: Venlafaxine, mirtazapine etc.

Trazodone Bupropion Venlafaxine

 Chemistry of Antidepressants
C. Selective serotonin reuptake inhibitors (SSRIs):
SSRIs are effective and more selective antidepressants (selective serotonin reuptake
inhibitors) with minimal autonomic toxicity. All are structurally distinct from the tricyclic
molecules. E.g. Fluoxetine, Sertraline, citalopram etc.

Fluoxetine
Phenelzine
D. Monoamine oxidase (MAO inhibitors):
MAO inhibitors may be classified as hydrazides, exemplified by the C-N-N moiety, as in
the case with phenelzine or nonhydrazides, which lack such a moiety, as with
tranylcypromine.

Tranylcypromine
 Serotonergic Receptors
Receptors Location and Actions

 5-HT1 Brain, Raphe nuclei

5-HT1A, 5-HT1B, 5-HT1D, 5-
HT1E, 5-HT1F, 5-HT1P

 5-HT2 Platelet aggregation and

5-HT2A smooth muscle contraction
5-HT2B
5-HT2C

 5-HT3 Gastrointestinal tract,

area postrema; vomiting

 5-HT4 Gastrointestinal tract; brain;

secretion and peristalsis

 5-HT5A,B Brain;
 5-HT6,7 Brain; 5-HT6 high affinity for
antidepressant drugs
Parkinsonism
Simplified diagram showing mechanisms believed to be involved in the pathophysiology of depression. The main prodepressive pathways
involve the hypothalamic-pituitary-adrenal axis, which is activated by stress and in turn enhances the excitotoxic action of glutamate,
mediated by NMDA receptors (see Ch. 33), and switches on the expression of genes that promote neural apoptosis in the hippocampus and
prefrontal cortex. The antidepressive pathways involve the monoamines noradrenaline (NA) and 5-hydroxytryptamine (5-HT), which act on G-
protein-coupled receptors, and the brain-derived neurotrophic factor (BDNF), which acts on a kinase-linked receptor (TrkB), switching on
genes that protect neurons against apoptosis and also promote neurogenesis. ACTH, adrenocorticotrophic hormone; CRF, corticotrophin-
releasing factor. Rang-Del
Excitotoxic: degree of toxicity
to nerve cells: the degree to
which a substance is believed
to be toxic to nerve cells
through excessive stimulation.