ANTIDEPRESSANT DRUGS

1. Antidepressants and
Pathophysiology of depression

3. TYPES OF ANTIDEPRESSANT DRUG
Antidepressant drugs fall into the following categories.
• inhibitors of monoamine uptake:
• non-selective (noradrenaline/serotonin) uptake inhibitors; these
include tricyclic antidepressants (TCAs) (e.g. imipramine,
amitriptyline) and more recent antidepressants such as venlafaxine
(somewhat selective for serotonin) and duloxetine, which have
fewer side effects than TCAs.
• selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine,
fluvoxamine, paroxetine and sertraline).
• selective noradrenaline uptake inhibitors (e.g. maprotiline,
reboxetine).

4. Neurotrophic Hypothesis
• Depression is associated with the loss of
neurotrophic support and that effective
antidepressant therapies increase
neurogenesis and synaptic connectivity in
cortical areas such as the hippocampus. Brain
derived neurotrophic factor (BDNF) is thought
to exert its influence on neuronal survival and
growth effects by activating the tyrosine
kinase receptor B in both neurons and glia

6. Neuroendocrine factors in depression
• Depression is known to be associated with a
number of hormonal abnormalities. Among
the most replicated of these findings are
abnormalities in the HPA axis in patients with
MDD. Moreover, MDD is associated with
elevated cortisol levels, nonsuppression of
adrenocorticotropic hormone (ACTH) release,
and chronically elevated levels of
corticotropin-releasing hormone.

7. • The significance of these HPA abnormalities is
unclear, but they are thought to indicate a
dysregulation of the stress hormone axis. More
severe types of depression, such as psychotic
depression, tend to be associated with HPA
abnormalities more commonly than milder forms
of major depression. It is well known that both
exogenous glucocorticoids and endogenous
elevation of cortisol are associated with mood
symptoms and cognitive deficits similar to those
seen in MDD.

8. • Thyroid dysregulation has also been reported
in depressed patients. Up to 25% of depressed
patients are reported to have abnormal
thyroid function. Thyroid hormones (TH) have
a profound influence on behavior and mood,
and appear to be capable of modulating major
affective illness. Thyroid supplementation is
now widely accepted as an effective
treatment option for patients with affective
disorders.

9. • Sex steroids are also implicated in the
pathophysiology of depression. Estrogen
deficiency states, which occur in the
postpartum and postmenopausal periods, are
thought to play a role in the aetiology of
depression in some women. Likewise, severe
testosterone deficiency in men is sometimes
associated with depressive symptoms.

10. • It is evident that the monoamine,
neuroendocrine, and neurotrophic systems are
interrelated in important ways. For example, HPA
and steroid abnormalities may contribute to
suppression of transcription of the BDNF gene.
Glucocorticoid receptors are found in high
density in the hippocampus. Binding of these
hippocampal glucocorticoid receptors by cortisol
during chronic stress states such as major
depression may decrease BDNF

11. • BDNF synthesis and may result in volume loss
in stress-sensitive regions such as the
hippocampus. The chronic activation of
monoamine receptors by antidepressants
appears to have the opposite effect of stress
and results in an increase in BDNF tran-
scription. In addition, activation of
monoamine receptors appears to down-
regulate the HPA axis and may normalize HPA
function.

12. Monoamine oxidase Inhibitors
• The first class of drugs with relatively specific
antidepressant effects were the MAOIs.
• Iproniazid, which was developed initially for the
treatment of tuberculosis, was found to have
mood-elevating effects in patients with
tuberculosis. Subsequently, iproniazid was shown
to inhibit MAO, leading to the development of
additional MAOIs including phenelzine,
isocarboxazid, and tranylcypromine.

13. Monoamine oxidase
• Monoamine oxidase is found in nearly all tissues,
and exists in two similar molecular forms coded
by separate genes.
• MAO-A has a substrate preference for 5-HT and is
the main target for the antidepressant MAOIs.
• MAO-B has a substrate preference for
phenylethylamine, and both enzymes act on
noradrenaline and dopamine. Type B is
selectively inhibited by selegiline, which is used
in the treatment of parkinsonism.

14. • Disruption of the MAO-A gene in mice causes
increased brain accumulation of 5-HT and, to a
lesser extent, noradrenaline, along with
aggressive behaviour.
• Most antidepressant MAOIs act on both forms of
MAO, but clinical studies with subtype-specific
inhibitors have shown clearly that antidepressant
activity, as well as the main side effects of MAOIs,
is associated with MAO-A inhibition. MAO is
located intracellularly, mostly associated with
mitochondria, and has two main functions.

15. Table: Substrates and inhibitors for type A and
type B monoamine oxidase
Type A Type B
Preferred substrates Noradrenaline 5-
Hydroxytryptamine
Phenylethylamine Benzylamine
Non-specific substrates Dopamine
Tyramine
Dopamine
Tyramine
Specific inhibitors Clorgiline
Moclobemide
Selegiline
Non-specific
inhibitors
Pargyline
Tranylcypromine
Isocarboxazid
Pargyline
Tranylcypromine
Isocarboxazid

16. • The MAOI’s nonselectively and irreversibly inhibit
both MAO-A and MAO-B, which are located in the
mitochondria and metabolize (inactivate)
monoamines, including 5-HT and NE .
• Within nerve terminals, MAO regulates the free
intraneuronal concentration of noradrenaline or
5-HT, and hence the releasable stores of these
transmitters. It is not involved in the inactivation
of released transmitter.

17. • MAO is important in the inactivation of
endogenous and ingested amines that would
otherwise produce unwanted effects. An
example is tyramine, an ingested amine that is
a substrate for both MAO-A and MAO-B, and
is important in producing some clinically
important adverse interactions of MAOIs with
foods and other drugs.

18. Pharmacokinetics
• MAOIs are metabolized by acetylation, although
the end products are incompletely characterized.
A significant portion of the population (50% of
the Caucasian population and an even higher
percentage among Asians) are "slow acetylators"
and will exhibit elevated plasma levels.
• The nonselective MAOIs used in the treatment of
depression are irreversible (sometimes called
"suicide") inhibitors; thus, it takes up to 2 weeks
for MAO activity to recover, even though the
parent drug is excreted within 24 hours

19. • Recovery of normal enzyme function is
dependent on synthesis and transport of new
MAO to monoaminergic nerve terminals.
Despite this irreversible enzyme inhibition,
MAOIs require daily dosing.

20. Pharmacological actions
• MAOIs do not increase the response of peripheral
organs, such as the heart and blood vessels, to
sympathetic nerve stimulation.
• The main effect of MAOIs is to increase the cytoplasmic
concentration of monoamines in nerve terminals,
without greatly affecting the vesicular stores that form
the pool that is releasable by nerve stimulation. The
increased cytoplasmic pool results in an increased rate
of spontaneous leakage of monoamines, and also an
increased release by indirectly acting sympathomimetic
amines such as amphetamine and tyramine

21. • This occurs because these amines work by
displacing noradrenaline from the vesicles into
the nerve terminal cytoplasm, from which it
may either leak out and produce a response,
or be degraded by MAO
• In normal human subjects, MAOIs cause an
immediate increase in motor activity, and
euphoria and excitement develop over the
course of a few days.

22. • The effects of MAOIs on amine metabolism
develop rapidly, and the effect of a single dose
lasts for several days
• MAOIs cause a delayed down-regulation of β-
adrenoceptors and 5-HT2-receptors

23. Hydrazine derivatives
Phenelzine and isocarboxazid
Non- hydrazines derivatives
Tranylcypromine, selegiline and meclobemide
The hydrazines and tranylcypromine are
irreversible and non selective MAOI’s

24. • Meclobemide is reversible and selective
inhibitor of MAO-A but it can be displaced
from MAO-A by tyramine, and this increases
the risk of drug-food interaction. (Tyramine is
often produced by decarboxylation of tyrosine
during fermentation or decay, mostly present
in cheese, meat and fish)
• Selegiline is an irreversible MAO-B specific
drug and used in parkinsonism

25. Side effects
• Hypotension is a common side effect. One
possible explanation for this effect-the opposite
of what might have been expected-is that amines
such as dopamine or octopamine accumulate
within peripheral sympathetic nerve terminals
and displace noradrenaline from the storage
vesicles, thus reducing noradrenaline release
associated with sympathetic activity. Octopamine
acts as false transmitter and causing minimal
activity of alpha and beta receptors.

26. • Excessive central stimulation may cause tremors,
excitement, insomnia and, in overdose,
convulsions.
• Increased appetite, leading to weight gain, can be
so extreme as to require the drug to be
discontinued.
• Atropine-like side effects (dry mouth, blurred
vision, urinary retention, etc.) are common with
MAOIs, although they are less of a problem than
with TCAs.

27. Interaction with other drugs and foods
• The cheese reaction is a direct consequence of
MAO inhibition and occurs when normally
innocuous amines (mainly tyramine) produced
during fermentation are ingested. Tyramine is
normally metabolised by MAO in the gut wall
and liver, and little dietary tyramine reaches
the systemic circulation. MAO inhibition
allows tyramine to be absorbed, and also
enhances its sympathomimetic effect

28. • The result is acute hypertension, giving rise to
a severe throbbing headache and occasionally
even to intracranial haemorrhage
• Administration of indirectly acting
sympathomimetic amines (e.g. ephedrine,
amphetamine) also causes severe
hypertension in patients receiving MAOIs

29. • Moclobemide, a specific MAO-A inhibitor,
does not cause the cheese reaction, probably
because tyramine can still be metabolised by
MAO-B.

30. Tricyclic Antidepressants
• Tricyclic antidepressants are closely related in
structure to the phenothiazines and were
initially synthesised (in 1949) as potential
antipsychotic drugs. Imipramine was found to
be of no use in schizophrenia but effective in
depression, so related compounds, such as
clomipramine, were synthesised. They differ
from phenothiazines principally in the
incorporation of an extra atom into the central
ring.

31. • The main immediate effect of TCAs is to block the
uptake of amines by nerve terminals, by competition
for the binding site of the amine transporter.
• Synthesis of amines, storage in synaptic vesicles, and
release are not directly affected, although some TCAs
appear to increase transmitter release indirectly by
blocking presynaptic α2- adrenoceptors. Most TCAs
inhibit noradrenaline and 5-HT uptake by brain
synaptosomes to a similar degree but have much less
effect on dopamine uptake.

32. • The major metabolites of TCAs have considerable
pharmacological activity (in some cases greater
than that of the parent drug) and often differ
from the parent drug in respect of their
noradrenaline/5-HT selectivity
• In addition to their effects on amine uptake, most
TCAs affect one or more types of
neurotransmitter receptor, including muscarinic
acetylcholine receptors, histamine receptors and
5-HT receptors.
• TCAs are also used to treat neuropathic pain

33. Pharmacokinetics
• Tricyclic antidepressants are metabolised in the
liver by two main routes, namely N-
demethylation, whereby tertiary amines are
converted to secondary amines (e.g. imipramine
to desmethylimipramine, amitriptyline to
nortriptyline), and ring hydroxylation
• The TCAs, or their active metabolites, have
plasma exposure half-lives of 8-80 hours; this
makes once-daily dosing possible for most of the
compounds.

34. • Steady-state concentrations occur within
several days to several weeks of beginning
treatment. TCAs are largely eliminated by
hepatic CYPs
• Determination of plasma levels may be useful
in identifying patients who appear to have
toxic effects and may have excessively high
levels of the drug, or those in whom lack of
absorption or noncompliance is suspected.

35. • Dosage adjustments of TCAs are typically made
according to patient's clinical response, not based on
plasma levels. Nonetheless, monitoring the plasma
exposure has an important relationship to treatment
response: there is a relatively narrow therapeutic
window
• About 7% of patients metabolize TCAs slowly due to a
variant CYP2D6 isoenzyme, causing a 30-fold difference
in plasma concentrations among different patients
given the same TCA dose. To avoid toxicity in "slow
metabolizers," plasma levels should be monitored and
doses adjusted downward.

36. Side effects
• TCAs are potent antagonists at histamine H1
receptors; H1 receptor antagonism contributes to
the sedative effects of TCAs.
• Antagonism of muscarinic acetylcholine receptors
contributes to cognitive dulling as well as a range
of adverse effects mediated by the
parasympathetic nervous system (blurred vision,
dry mouth, tachycardia, constipation, difficulty
urinating). Some tolerance does occur for these
anticholinergic effects.

37. • Antagonism of alpha1 adrenergic receptors contributes
to orthostatic hypotension and sedation. Weight gain is
another side effect of this class of antidepressants.
• TCAs also have quinidine-like effects on cardiac
conduction that can be life threatening with overdose
and limit the use of TCAs in patients with coronary
heart disease. This is the primary reason that no more
than a one-week supply should be provided to a new
patient; even during maintenance treatment.
• Like other antidepressant drugs, TCAs also lower the
seizure threshold

38. Interactions with other drugs
• TCA’s rely on hepatic microsomal metabolism for
elimination, and this may be inhibited by
competing drugs (e.g. antipsychotic drugs and
some steroids).
• Tricyclic antidepressants potentiate the effects of
alcohol and anesthetic agents, for reasons that
are not well understood, and deaths have
occurred as a result of this, when severe
respiratory depression has followed a bout of
drinking.

39. • TCAs also interfere with the action of various
antihypertensive drugs with potentially
dangerous consequences, so their use in
hypertensive patients requires close
monitoring.

40. Acute toxicity
• Tricyclic antidepressants are dangerous in overdose, and were at
one time commonly used for suicide attempts, which was an
important factor prompting the introduction of safer
antidepressants.
• The main effects are on the central nervous system and the heart.
The initial effect of TCA overdosage is to cause excitement and
delirium, which may be accompanied by convulsions.
• This is followed by coma and respiratory depression lasting for
some days. Atropine-like effects are pronounced, including flushing,
dry mouth and skin, mydriasis, and inhibition of gut and bladder.
Anticholinesterase drugs have been used to counter atropine-like
effects but are no longer recommended. Cardiac dysrhythmias (see
above) are common, and sudden death (rare) may occur from
ventricular fibrillation.

41. Selective serotonin reuptake inhibitors
• A number of SSRIs were introduced from 1984-
1997, including fluoxetine, paroxetine, sertraline,
citalopram, escitalopram, and fluvoxamine; the
FDA has approved fluvoxamine for treatment of
obsessive-compulsive disorder and social anxiety
disorder, but not depression. All of the SSRIs
show a clear improvement in safety margin
compared to the TCAs and are much safer in
overdose, and in clinical practice have affected a
broad range of psychiatric, behavioral, and
medical conditions, for which they are used, on
and off label.

42. • SERT mediates the reuptake of serotonin into the
presynaptic terminal; neuronal uptake is the primary
process by which neurotransmission via 5-HT is
terminated. Thus, treatment with an SSRI initially
blocks reuptake and results in enhanced and prolonged
serotonergic neurotransmission. SSRIs used clinically
are relatively selective, that is, 10-fold or more, for
inhibition of SERT relative to NET. Increased synaptic
availability of serotonin stimulates a large number of
postsynaptic 5-HT receptor subtypes, as well as
somatodendritic and presynaptic terminal receptors
that regulate serotoninergic neuron activity and
serotonin release.

43. Pharmacokinetics
• All of the SSRIs are orally active and possess elimination
half-lives consistent with once-daily dosing. In the case of
fluoxetine, the combined action of the parent and the
desmethyl metabolite norfluoxetine allows for a once
weekly formulation. CYP2D6 is involved in the metabolism
of most SSRIs and the SSRIs are at least moderately potent
inhibitors of this isoenzyme. This creates a significant
potential for drug interaction for post-menopausal women
taking the breast cancer drug and estrogen antagonist,
tamoxifen ; the parent molecule is converted to a more
active metabolite by CYP2D6, and SSRIs may inhibit this
activation and diminish the therapeutic activity of
tamoxifen.

44. • Since venlafaxine and desvenlafaxine are weak
inhibitors of CYP2D6, these antidepressants
are not contraindicated in this clinical
situation. However, care should be used in
combining SSRIs with drugs that are
metabolized by CYPs 1A2, 2D6, 2C9, and 3A4
(e.g., warfarin, tricyclic antidepressants,
paclitaxel).

45. • Common side effects are nausea, anorexia,
insomnia, loss of libido.
• In combination with MAOIs, SSRIs can cause a
'serotonin syndrome' characterised by tremor,
hyperthermia and cardiovascular collapse,
from which deaths have occurred.

46. • There have been reports of increased
aggression, and occasionally violence, in
patients treated with fluoxetine, but these
have not been confirmed by controlled
studies. The use of SSRIs is not recommended
for treating depression in children under 18, in
whom efficacy is doubtful and adverse effects,
including excitement, insomnia and aggression
in the first few weeks of treatment, may occur.

47. Norepinephrine serotonin reuptake
inhibitors
• Four medications with a non-tricyclic structure
that inhibit the reuptake of both 5-HT and
norepinephrine have been approved for use in
the U.S. for treatment of depression, anxiety
disorders, and pain: venlafaxine and its
demethylated metabolite, desvenlafaxine;
duloxetine; and milnacipran (approved only
for fibromyalgia pain in the U.S.)

48. • SNRIs inhibit both SERT and NET. Depending
on the drug, the dose, and the potency at
each site, SNRIs cause enhanced serotonergic
and/or noradrenergic neurotransmission. The
enhanced serotonin concentration in the
synapse can interact with postsynaptic 5-HT
receptors.

49. • SNRI venlafaxine are first-line treatments for
most types of anxiety disorders, except when an
acute drug effect is desired. SNRIs are beneficial
in specific anxiety conditions such as generalized
anxiety disorder, social phobias, obsessive-
compulsive disorder, and panic disorder. These
effects appear to be related to the capacity of
serotonin to regulate the activity of brain
structures such as amygdala and locus coeruleus
that are thought to be involved in the genesis of
anxiety.

50. • The SNRIs have desirable safety advantages over
the TCAs . SNRIs have a side effect profile similar
to that of the SSRIs, including nausea,
constipation, insomnia, headaches, and sexual
dysfunction. The immediate release formulation
of venlafaxine can induce sustained diastolic
hypertension; this risk is reduced with the
extended-release form. This effect of venlafaxine
may not be associated simply with inhibition of
NET, since duloxetine does not share this side
effect.